Search

Targeted therapy resistance frequently develops in melanoma due to intratumor heterogeneity and epigenetic reprogramming. This also typically induces cross-resistance to immunotherapies. Whether this includes additional modes of therapy has not been fully assessed. We show that co-treatments of MAPKi with VSV-based oncolytics do not function in a synergistic fashion; rather, the MAPKis block infection. Melanoma resistance to vemurafenib further perturbs the cells’ ability to be infected by oncolytic viruses. Resistance to vemurafenib can be induced by the loss of SOX10, a common proliferative marker in melanoma. The loss of SOX10 promotes a cross-resistant state by further inhibiting viral infection and replication. Analysis of RNA-seq datasets revealed an upregulation of interferon-stimulated genes (ISGs) in SOX10 knockout populations and targeted therapy-resistant cells. Interestingly, the induction of ISGs appears to be independent of type I IFN production. Overall, our data suggest that the pathway mediating oncolytic resistance is due to the loss of SOX10 during acquired drug resistance in melanoma.

The phenomenal migratory and differentiation capacity of neural crest cells has been well established across model organisms. While the earliest stages of neural crest development have been investigated in non-mammalian model systems such as Xenopus and Aves, the early specification of this cell population has not been evaluated in mammalian embryos, of which the murine model is the most prevalent. Towards a more comprehensive understanding of mammalian neural crest formation and human comparative studies, we have used the rabbit as a mammalian system for the study of early neural crest specification and development. We examine the expression profile of well-characterized neural crest markers in rabbit embryos across developmental time from early gastrula to later neurula stages, and provide a comparison to markers of migratory neural crest in the chick. Importantly, we apply explant specification assays to address the pivotal question of mammalian neural crest ontogeny, and provide the first evidence that a specified population of neural crest cells exists in the rabbit gastrula prior to the overt expression of neural crest markers. Finally, we demonstrate that FGF signaling is necessary for early rabbit neural crest formation, as SU5402 treatment strongly represses neural crest marker expression in explant assays. This study pioneers the rabbit as a model for neural crest development, and provides the first demonstration of mammalian neural crest specification and the requirement of FGF signaling in this process.

Abstract Vemurafenib‐induced drug resistance in melanoma has been linked to receptor tyrosine kinase (RTK) upregulation. The MITF and SOX10 genes play roles as master regulators of melanocyte and melanoma development. Here, we aimed to explore the complex mechanisms behind the MITF/SOX10‐controlled RTK‐induced drug resistance in melanoma. To achieve this, we used a number of molecular techniques, including melanoma patient data from TCGA, vemurafenib‐resistant melanoma cell lines, and knock‐down studies. The melanoma cell lines were classified as proliferative or invasive based upon their MITF/AXL expression activity. We measured the change of expression activity for MITF/SOX10 and their receptor (AXL/ERBB3) and ligand (NRG1/GAS6) targets known to be involved in RTK‐induced drug resistance after vemurafenib treatment. We find that melanoma cell lines characterized as proliferative (high MITF low AXL), transform into an invasive (low MITF, high AXL) cell state after vemurafenib resistance, indicating novel feedback loops and advanced compensatory regulation mechanisms between the master regulators, receptors, and ligands involved in vemurafenib‐induced resistance. Together, our data disclose fine‐tuned mechanisms involved in RTK‐facilitated vemurafenib resistance that will be challenging to overcome by using single drug targeting strategies against melanoma.

Certain cranial neural crest cells are uniquely endowed with the ability to make skeletal cell types otherwise only derived from mesoderm. As these cells migrate into the pharyngeal arches, they downregulate neural crest specifier genes and upregulate socalled ectomesenchyme genes that are characteristic of skeletal progenitors. Although both external and intrinsic factors have been proposed as triggers of this transition, the details remain obscure. Here, we report the Nr2f nuclear receptors as intrinsic activators of the ectomesenchyme program: zebrafish nr2f5 single and nr2f2;nr2f5 double mutants show marked delays in upregulation of ectomesenchyme genes, such as dlx2a, prrx1a, prrx1b, sox9a, twist1a and fli1a, and in downregulation of sox10, which is normally restricted to early neural crest and non-ectomesenchyme lineages. Mutation of sox10 fully rescued skeletal development in nr2f5 single but not nr2f2;nr2f5 double mutants, but the initial ectomesenchyme delay persisted in both. Sox10 perdurance thus antagonizes the recovery but does not explain the impaired ectomesenchyme transition. Unraveling the mechanisms of Nr2f function will help solve the enduring puzzle of how cranial neural crest cells transition to the skeletal progenitor state. [ABSTRACT FROM AUTHOR]

Introduction: Metastatic cancers are frequently detected on fine-needle aspiration (FNA) cytology, and confirmation of metastatic breast cancer often requires immunocytochemistry. Tissue provisioning for FNA specimens is important. In this study, GATA3, gross cystic disease fluid protein-15 (GCDFP15), mammaglobin (MMG), and SOX10 were performed on cell block preparations from aspirates of histologically confirmed metastatic breast cancers. The diagnostic performance of single markers and combinations of these markers were investigated with the aim to construct a tissue-efficient immunopanel. Methodology: Aspirates of metastatic breast cancer with corresponding histology and biomarker (estrogen receptor (ER), progesterone receptor (PR), HER2 and ki67) profile were retrieved. ER, GATA3, GCDFP15, MMG and SOX10 immunostains were performed on cell block sections and their expressions were assessed and compared. Results: Immunostaining was performed on a total of 115 aspirates. GATA3 showed the highest expression, followed by MMG, GCDFP15 and SOX10. Twenty-three, five and five cases expressed GATA3, MMG and SOX10 only. The five cases expressing SOX10 only were ER negative, and SOX10 expression was negatively associated with ER (p = 0.001), MMG (p = 0.001), GCDFP15 (p = 0.010) and GATA3 (p = 0.002), whereas GATA3 expression showed positive correlation with ER positivity (p < 0.001). MMG and GCDFP15 showed association with high Ki67 (p < 0.05), and no correlations were found with HER2 expression. Conclusion: In this cohort, GATA3 was the most sensitive single marker. The addition of MMG and SOX10 increases the sensitivity for detection of ER positive and ER negative breast cancers, respectively. These findings support the use of a combination of GATA3/MMG/SOX10 for confirmation of metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Background: Waardenburg syndrome (WS) is a hereditary, genetically heterogeneous disorder characterized by variable presentations of sensorineural hearing impairment and pigmentation anomalies. This study aimed to investigate the clinical features of WS in detail and determine the genetic causes of patients with clinically suspected WS. Methods: A total of 24 patients from 21 Han‐Taiwanese families were enrolled and underwent comprehensive physical and audiological examinations. We applied targeted next‐generation sequencing (NGS) to investigate the potential causative variants in these patients and further validated the candidate variants through Sanger sequencing. Results: We identified 19 causative variants of WS in our cohort. Of these variants, nine were novel and discovered in PAX3, SOX10, EDNRB, and MITF genes, including missense, nonsense, deletion, and splice site variants. Several patients presented with skeletal deformities, hypotonia, megacolon, and neurological disorders that were rarely seen in WS. Conclusion: This study revealed highly phenotypic variability in Taiwanese WS patients and demonstrated that targeted NGS allowed us to clarify the genetic diagnosis and extend the genetic variant spectrum of WS. [ABSTRACT FROM AUTHOR]

The proneural transcription factor Achaete-scute complex-like 1 (Ascl1) is a major regulator of neural fate decisions, implicated both in neurogenesis and oligodendrogliogenesis. Focusing on its neurogenic activity, Ascl1 has been widely used to reprogram non-neuronal cells into induced neurons. In vitro, Ascl1 induces efficient reprogramming of proliferative astroglia from the early postnatal cerebral cortex into interneuron-like cells. Here, we examined whether Ascl1 can similarly induce neuronal reprogramming of glia undergoing proliferation in the postnatal mouse cerebral cortex in vivo. Toward this goal, we targeted cortical glia during the peak of proliferative expansion (i.e., postnatal day 5) by injecting a retrovirus encoding for Ascl1 into the mouse cerebral cortex. In contrast to the efficient reprogramming observed in vitro, in vivo Ascl1-transduced glial cells were converted into doublecortin-immunoreactive neurons only with very low efficiency. However, we noted a drastic shift in the relative number of retrovirus-transduced Sox10-positive oligodendrocyte progenitor cells (OPCs) as compared to glial fibrillary acidic protein (GFAP)-positive astrocytes. Genetic fate mapping demonstrated that this increase in OPCs was not due to Ascl1-mediated astrocyte-to-OPC fate conversion. Rather, EdU incorporation experiments revealed that Ascl1 caused a selective increase in proliferative activity of OPCs, but not astrocytes. Our data indicate that rather than inducing neuronal reprogramming of glia in the early postnatal cortex, Ascl1 is a selective enhancer of OPC proliferation. [ABSTRACT FROM AUTHOR]

Gliomas, originating from the glial cells, are the most lethal type of primary tumors in the central nervous system. Standard treatments like surgery have not significantly improved the prognosis of glioblastoma patients. Recently, immune therapy has become a novel and effective option. As a conserved group of transcriptional regulators, the Sry-type HMG box (SOX) family has been proved to have a correlation with numerous diseases. Based on the large-scale machine learning, we found that the SOX family, with significant immune characteristics and genomic profiles, can be divided into two distinct clusters in gliomas, among which SOX10 was identified as an excellent immune regulator of macrophage in gliomas. The high expression of SOX10 is related to a shorter OS in LGG, HGG, and pan-cancer groups but benefited from the immunotherapy. It turned out in single-cell sequencing that SOX10 is high in neurons, M1 macrophages, and neural stem cells. Also, macrophages are found to be elevated in the SOX10 high-expression group. SOX10 has a positive correlation with macrophage cytokine production and negative regulation of macrophages’ chemotaxis and migration. In conclusion, our study demonstrates the outstanding cluster ability of the SOX family, indicating that SOX10 is an immune regulator of macrophage in gliomas, which can be an effective target for glioma immunotherapy. [ABSTRACT FROM AUTHOR]

Objectives: SOX10 expression helps identify melanocytic lesions. Over time, novel uses have been identified, such as expression in triple-negative breast cancer (TNBC). We evaluated the usefulness of SOX10 in breast pathology-specifically, identification and subtyping of TNBC and distinction from gynecologic carcinomas, use as a myoepithelial marker, and in the distinction of usual ductal hyperplasia (UDH) from atypical ductal hyperplasia (ADH).Methods: Several breast and gynecologic carcinoma tissue microarrays containing a total of 492 cases were stained with SOX10. Whole sections of 34 ADH, 50 UDH, and 29 ductal carcinoma in situ (DCIS) samples were also stained with SOX10.Results: SOX10 expression was identified in 67% of consecutive TNBC cases. Expression was mostly seen in nonapocrine, androgen receptor (AR)-negative TNBCs. All gynecologic carcinomas (n = 157) were negative. All UDH cases showed mosaic SOX10 expression, while all ADH cases lacked expression. All estrogen receptor (ER)-positive DCIS (n = 19) specimens were negative for SOX10, while 2 of 10 ER-negative DCIS specimens were positive for SOX10. The latter 2 cases showed SOX10-positive invasive carcinomas.Conclusions: SOX10 identifies nonluminal AR-type TNBC and is useful in distinguishing TNBC from gynecologic carcinomas. SOX10 can distinguish UDH from ADH. SOX10 is not useful in distinguishing ADH from DCIS. [ABSTRACT FROM AUTHOR]

Melanocyte-derived tumours are common in humans and animals and their spontaneous occurrence in dogs and the clinicopathological progression in malignant presentations is comparable with humans. Melanomas are a heterogeneous group of malignant neoplasms and several subtypes have been classified, including angiomatoid melanoma, of which only five cases have been reported in humans but none in animals. We now document cases of primary angiomatoid melanoma in the skin and oral cavity of two dogs. Neoplastic cells resembling endothelial cells that lined large blood vessels in the tumours were immunonegative for CD34 but intensely positive for SOX10. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Waardenburg syndrome (WS) is a rare genetic disorder characterized by musculoskeletal abnormalities, deafness and hypopigmentation of hair and skin. This article’s aim is to investigate clinical and genetic characteristics of WS in three unrelated Caucasian individuals. Case presentation The first patient was a 25-year-old female with congenital bilateral hearing loss, bright-blue-eyes, hypopigmentation of hair and skin, megacolon, language retardation, tenosynovitis and neuromas. The second case was an infant symptomatic from birth, with dysphagia, Hirschsprung disease and neurological abnormalities. The third patient was a 14-year-old boy with congenital bilateral hearing loss and ileocolic Hirschsprung disease. In order to identify variants in potentially causal genes of the patients’ phenotype, genetical testing was conducted: targeted clinical exome, targeted exome and trio exome, respectively. We identified three novel variants spread throughout the coding sequence of SOX10. The c.395C>G variant identified de novo in patient 1 was a single nucleotide substitution in exon 2. The c.850G>T variant identified as heterozygous in patient 2 was a loss-of-function variant that generated a premature stop codon. The c.966dupT variant identified in patient 3 was a duplication that generated a premature stop codon. It had been identified in his father, arising a possible germinal mosaicism. According to in silico predictors the variant identified in patient 1 was considered as pathogenic, whereas the other two were classified as likely pathogenic. Conclusions An exact description of the mutations responsible for WS provides useful information to explain clinical features of WS and contributes to better genetic counselling of WS patients.

Abstract Background Waardenburg syndrome (WS) is a hereditary, genetically heterogeneous disorder characterized by variable presentations of sensorineural hearing impairment and pigmentation anomalies. This study aimed to investigate the clinical features of WS in detail and determine the genetic causes of patients with clinically suspected WS. Methods A total of 24 patients from 21 Han‐Taiwanese families were enrolled and underwent comprehensive physical and audiological examinations. We applied targeted next‐generation sequencing (NGS) to investigate the potential causative variants in these patients and further validated the candidate variants through Sanger sequencing. Results We identified 19 causative variants of WS in our cohort. Of these variants, nine were novel and discovered in PAX3, SOX10, EDNRB, and MITF genes, including missense, nonsense, deletion, and splice site variants. Several patients presented with skeletal deformities, hypotonia, megacolon, and neurological disorders that were rarely seen in WS. Conclusion This study revealed highly phenotypic variability in Taiwanese WS patients and demonstrated that targeted NGS allowed us to clarify the genetic diagnosis and extend the genetic variant spectrum of WS.

Background: Waardenburg syndrome (WS) is a rare genetic disorder characterized by congenital sensorineural hearing loss and pigmentary abnormalities of the hair, skin and eyes. However, exotropia is rarely reported. The purpose of this study is to describe the clinical characteristics of three sporadic patients with WS and congenital exotropia and to investigate the disease-causing genes for them. Methods: Patients underwent detailed physical and ocular examinations. Ocular alignment and binocular status were evaluated. DNA was extracted and whole exome sequencing was performed to detect the pathogenic variations in the disease-causing genes for WS. Cloning sequencing was carried out for those indel variations. Results: Three unrelated patients were diagnosed with Waardenburg syndrome and congenital exotropia. Four novel variants, including c.136delA (p.I46Sfs*64) and c.668G>T (p.R223L) in PAX3, c.709dupC (p.Q237Pfs*119) in COL11A2, c.426G>A (p.W142X) in SOX10 gene, were detected in this study. Conclusion: Simultaneous presence of congenital exotropia and WS in our patients is suggested that WS could be involved in malfunction in the multiple nerve systems. Our genetic study will expand the mutation spectrum of PAX3, COL11A2 and SOX10 genes, and is helpful for further study on the molecular pathogenesis of WS. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI) induces neuroma formation at the severed nerve stump resulting in impaired nerve regeneration and functional recovery in patients. So far, molecular mechanisms and cell types present in the neuroma impeding on regeneration have only sparsely been analyzed. Herein we compare resected human neuroma tissue with intact donor nerves from the same patient. Neuroma from several post-injury timepoints (1-13 months) were included, thereby allowing for temporal correlation with molecular and cellular processes. We observed reduced axonal area and percentage of myelin producing Schwann cells (SCs) compared to intact nerves. However, total SOX10 positive SC numbers were comparable. Notably, markers for SCs in a repair mode including c-JUN, the low-affinity neurotrophin receptor (NTR) p75, SHH (sonic hedgehog) and SC proliferation (phospho-histone H3) were upregulated in neuroma, suggesting presence of SCs in repair status. In agreement, in neuroma, pro-regenerative markers such as phosphorylated i.e. activated CREB (pCREB), ATF3, GAP43 and SCG10 were upregulated. In addition, neuroma tissue was infiltrated by several types of macrophages. Finally, when taken in culture, neuroma SCs were indistinguishable from controls SCs with regard to proliferation and morphology. However, cultured neuroma SCs retained a different molecular signature from control SCs including increased inflammation and reduced gene expression for differentiation markers such as myelin genes. In summary, human neuroma tissue consists of SCs with a repair status and is infiltrated strongly by several types of macrophages., Competing Interests: Declaration of competing interest Declarations of interest: none., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: We have recently demonstrated that Sox10 -expressing ( Sox10 + ) cells give rise to mainly type-III neuronal taste bud cells that are responsible for sour and salt taste. The two tissue compartments containing Sox10 + cells in the surrounding of taste buds include the connective tissue core of taste papillae and von Ebner's glands (vEGs) that are connected to the trench of circumvallate and foliate papillae., Methods: In this study, we performed single cell RNA-sequencing of the epithelium of Sox10-Cre/tdT mouse circumvallate/vEG complex and used inducible Cre mouse models to map the cell lineages of vEGs and/or connective tissue (including stromal and Schwann cells)., Results: Transcriptomic analysis indicated that Sox10 expression was enriched in the cell clusters of vEG ducts that contained abundant proliferating cells, while Sox10-Cre/tdT expression was enriched in type-III taste bud cells and vEG ductal cells. In vivo lineage mapping showed that the traced cells were distributed in circumvallate taste buds concurrently with those in the vEGs, but not in the connective tissue. Moreover, multiple genes encoding pathogen receptors were enriched in the vEG ducts hosting Sox10 + cells., Discussion: Our data supports that it is the vEGs, not connective tissue core, that serve as the niche of Sox10 + taste bud progenitors. If this is also true in humans, our data indicates that vEG duct is a source of Sox10 + taste bud progenitors and susceptible to pathogen infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yu, Kastriti, Ishan, Choudhary, Rashid, Kramer, Do, Wang, Xu, Schwabe, Ye, Adameyko and Liu.)

The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from human induced pluripotent stem cell (hiPSC)-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from patients with MS, organoids properly mimic macroglia-microglia neurodegenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support the implementation of this organoid model for drug screening to halt inflammatory neurodegeneration., Competing Interests: Declaration of interests D.S.R.: research funding from Abata Therapeutics and Sanofi-Genzyme. P.A.C.: research funding from Genentech and previously Principia; consulting honoraria for serving on SABs for NervGen, Idorsia, Biogen, Vaccitech, and Lilly. L.S.: original organoid model(6) is under a patent by Johns Hopkins University, which is licensed to AxoSim, New Orleans, US; she consults for AxoSim. M.A.: consultancy fees from GSK, Sanofi, Biogen, Immunic Therapeutics, and Abata Therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Leucine-rich glioma-inactivated protein 1 (LGI1), a secretory protein in the brain, plays a critical role in myelination; dysfunction of this protein leads to hypomyelination and white matter abnormalities (WMAs). Here, we hypothesized that LGI1 may regulate myelination through binding to an unidentified receptor on the membrane of oligodendrocytes (OLs). To search for this hypothetic receptor, we analyzed LGI1 binding proteins through LGI1-3 × FLAG affinity chromatography with mouse brain lysates followed by mass spectrometry. An OL-specific membrane protein, the oligodendrocytic myelin paranodal and inner loop protein (OPALIN), was identified. Conditional knockout (cKO) of OPALIN in the OL lineage caused hypomyelination and WMAs, phenocopying LGI1 deficiency in mice. Biochemical analysis revealed the downregulation of Sox10 and Olig2, transcription factors critical for OL differentiation, further confirming the impaired OL maturation in Opalin cKO mice. Moreover, virus-mediated re-expression of OPALIN successfully restored myelination in Opalin cKO mice. In contrast, re-expression of LGI1-unbound OPALIN&#95;K23A/D26A failed to reverse the hypomyelination phenotype. In conclusion, our study demonstrated that OPALIN on the OL membrane serves as an LGI1 receptor, highlighting the importance of the LGI1/OPALIN complex in orchestrating OL differentiation and myelination., Competing Interests: Competing interests statement:The authors declare no competing interest.

Introduction: Kallmann syndrome (KS) is a genetically heterogeneous developmental disorder that most often manifests hypogonadotropic hypogonadism (HH) and hypo-/anosmia due to early embryonic impairment in the migration of gonadotropin-releasing hormone neurons. SOX10 (SRY-Box 10; MIM*602229), a key transcriptional activator involved in the development of neural crest cells, has been associated with KS and is identified as one of the causative genes of Waardenburg syndrome (WS)., Case Presentation: A 28-year-old female patient, who was clinically diagnosed with KS in her childhood, presented with HH and anosmia, mild bilateral sensorineural hearing loss (SNHL), and pigmentation abnormalities. Next-generation sequencing analysis detected a missense heterozygous SOX10 pathogenic variant (NM&#95;006941.4:c.506C>T) in the proposita and in her mother, whose phenotype included exclusively anosmia and hypopigmented skin patches. The same variant has been described by Pingault et al. [Clin Genet. 2015;88(4):352-9] in a patient with apparently isolated bilateral severe SNHL., Conclusion: Our finding substantiates the extreme phenotypic variability of SOX10 -related disorders, which range from classical KS and/or WS to contracted endophenotypes that could share a common pathway in the development of neural crest cells and highlights the need for careful evaluation and long-term follow-up of SOX10 patients, with special focus on atypical/additional and/or late-onset phenotypic traits., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Super-enhancer consists of a large cluster of transcription enhancers that regulates the expression of genes playing an important role in the growth and development of malignant tumors. Recently, several attempts for the identification of super-enhancers have been made, but their functional role in tumor cells remains unclear. This paper aims at elucidating the functional properties of KLF6 super-enhancer related to the growth regulation of HepG2 cells, in relation to transcription factors (TFs). First, some TFs specifying KLF6 super enhancer were identified using CRISPR/Cas9 system and siRNA. Then, their effects on the expression of the target gene KLF6 were assessed. Last, their influence on the proliferation of tumor cells was considered using the MTT method. The study shows that the active enhancers of KLF6 super-enhancer recruit GATA2 and SOX10 TFs to control the expression of the target gene, KLF6. Our findings suggest that the activity of KLF6 super-enhancer is regulated by two TFs (GATA2 and SOX10), and its targeting may be a potential therapeutic strategy for the liver cancer therapy. [ABSTRACT FROM AUTHOR]

Pathological changes of the cochlea and hearing loss have been well addressed in Waardenburg syndrome (WS). However, the vestibular organ malformation in WS is still largely unknown. In this study, the differentiation and development of vestibular sensory epithelium and vestibular function caused by SOX10 mutation, a critical gene induces WS, have been studied in minature pig model. Degeneration of vestibular hair cells was found in this Sox10 mutation porcine model. Inner ear phenotype of the SOX10+/R109W miniature pigs showed cochlear abnormalities as well as saccular hypofunction. In the mutant pigs, no prominent dissimilarity was shown in the bone structure of the semicircular canals. However, the saccular membrane was collapsed, and the infusion of stereocilia of the hair cells was observed. There were no dark cells in the utricles in the mutant pigs. The density of the utricular hair cells was also significantly lower in the mutant pigs compared to the wild type. Our study demonstrated that the SOX10 gene and melanocytes play important roles in the vestibular organ development. Sox10 mutation disrupts the KIT-DCT signaling pathway, affects the development of melanocytes, and leads to vestibule morphogenesis. [ABSTRACT FROM AUTHOR]

Background/aim: We aimed to elucidate the causes of the increased melanisation in basal cell carcinoma (BCC) and seborrheic keratosis (SK), and the role of melanocytes in this process. Materials and methods: This study was a retrospective-cohort study conducted in the pathology department of a university hospital between January 2019 and October 2020. Forty-nine SK and 30 pigmented BCC were included in our study. SRY-box transcription factor 10 (SOX10), CD68, and Masson-Fontana staining was used for analysis in all samples. A representative section of each specimen was photographed under ×400 magnification to facilitate the assessments of the morphology of the melanocytes and their following morphometric parameters: density, nuclear diameter, and distribution. The density of pigmented keratinocytes in the lesional epidermis was scored. The nuclear diameters of melanocytes located in the nonlesional epidermis, the density of the melanophages, and the presence or absence of ulceration and solar elastosis were also recorded. Results: The morphometric findings confirmed a statistically significant increase in melanocyte density in the BCC group compared with that in the SK group (p < 0.001). Moreover, the nuclear minor diameters in the melanocytes of the BCC sections were significantly higher than those in the SK specimens (p < 0.001). The epidermal melanocytes were distributed diffusely in almost all BCC specimens (96.7%), whereas they were mainly limited to the basal layer in the majority of the SK sections (59.2%). The number of epidermal melanised keratinocytes with a score of 3 was significantly higher in the SK group (n = 31; 63.2%) than in the BCC group (n = 6; 20%) (p = 0.001), and they were the main cells representing the pigmented appearance of the tumours. No significant difference was found between both tumour groups in terms of their melanophage density scores (p = 0.206). Conclusion: This study is the first step towards an objective quantification of the melanocytes in pigmented epithelial tumours and may provide a morphological background for future studies on these skin lesions. [ABSTRACT FROM AUTHOR]

Nerve sheath tumors are a group of tumors originating from Schwann cells, fibroblasts, and perineurial cells. In veterinary pathology, the terminology for nerve sheath tumors remains inconsistent, and many pathologists follow the human classification of such tumors in practice. Immunohistochemistry plays an important role in the diagnosis of nerve sheath tumors, but specific immunohistochemical and molecular biomarkers are lacking. In our study, we histopathologically reevaluated 79 canine nerve sheath tumors and assessed their reactivity for the immunohistochemical markers Sox10, claudin-1, GFAP, CNPase, and Ki-67. Based on the results, we classified the tumors according to the most recent human classification. Twelve cases were diagnosed as benign nerve sheath tumors, including six neurofibromas, three nerve sheath myxomas, two hybrid nerve sheath tumors (perineurioma/neurofibroma and perineurioma/schwannoma), and one schwannoma. Sixty-seven tumors were malignant nerve sheath tumors, including fifty-six conventional, four perineural, one epithelioid malignant nerve sheath tumor, and six malignant nerve sheath tumors with divergent differentiation. We believe that with the application of the proposed panel, an updated classification of canine nerve sheath tumors could largely follow the recent human WHO classification of tumors of the cranial and paraspinal nerves, but prospective studies would be needed to assess its prognostic value. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) is a subtype of primary cutaneous T-cell lymphoma (CTCL) with an indolent course that rarely progresses. Histologically, the lesions display a superficial lymphocytic infiltrate with epidermotropism of neoplastic T-cells. Hypopigmented MF is a rare variant that presents with hypopigmented lesions and is more likely to affect young patients. The etiology of the hypopigmentation is unclear. The aim of this study was to assess melanocyte loss in MF through immunohistochemistry (IHC) with SOX10. Twenty cases were evaluated, including seven of the hypopigmented subtype. The neoplastic epidermotropic infiltrate consisted predominantly of CD4+ T-cells in 65% of cases; CD8+ T-cells were present in moderate to abundant numbers in most cases. SOX10 IHC showed a decrease or focal complete loss of melanocytes in 50% of the cases. The predominant neoplastic cell type (CD4+/CD8+), age, race, gender, histologic features, and reported clinical pigmentation of the lesions were not predictive of melanocyte loss. A significant loss of melanocytes was observed in 43% of hypopigmented cases and 54% of conventional cases. Additional studies will increase our understanding of the relationship between observed pigmentation and the loss of melanocytes in MF.

Abstract Background Hereditary motor and sensory neuropathy, also referred to as Charcot–Marie–Tooth disease (CMT), is most often caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. This duplication causes CMT type 1A (CMT1A). CMT1A rarely occurs in combination with other hereditary neuromuscular disorders. However, such rare genetic coincidences produce a severe phenotype and have been reported in terms of “double trouble” overlapping syndrome. Waardenburg syndrome (WS) is the most common form of a hereditary syndromic deafness. It is primarily characterized by pigmentation anomalies and classified into four major phenotypes. A mutation in the SRY sex determining region Y-box 10 (SOX10) gene causes WS type 2 or 4 and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease. We describe a 11-year-old boy with extreme hypertrophic neuropathy because of a combination of CMT1A and WS type 2. This is the first published case on the co-occurrence of CMT1A and WS type 2. Case presentation The 11-year-old boy presented with motor developmental delay and a deterioration in unstable walking at 6 years of age. In addition, he had congenital hearing loss and heterochromia iridis. The neurological examination revealed weakness in the distal limbs with pes cavus. He was diagnosed with CMT1A by the fluorescence in situ hybridization method. His paternal pedigree had a history of CMT1A. However, no family member had congenital hearing loss. His clinical manifestation was apparently severe than those of his relatives with CMT1A. In addition, a whole-body magnetic resonance neurography revealed an extreme enlargement of his systemic cranial and spinal nerves. Subsequently, a genetic analysis revealed a heterozygous frameshift mutation c.876delT (p.F292Lfs*19) in the SOX10 gene. He was eventually diagnosed with WS type 2. Conclusions We described a patient with a genetically confirmed overlapping diagnoses of CMT1A and WS type 2. The double trouble with the genes created a significant impact on the peripheral nerves system. Severe phenotype in the proband can be attributed to the cumulative effect of mutations in both PMP22 and SOX10 genes, responsible for demyelinating neuropathy.

Abstract Background Approximately 5–10% of HER2-positive breast cancers can be defined by low expression of the Ste20-like kinase, SLK, and high expression of SOX10. Our lab has observed that genetic deletion of SLK results in the induction of Sox10 and significantly accelerates tumor initiation in a HER2-induced mammary tumor model. However, the mechanism responsible for the induction of SOX10 gene expression in this context remains unknown. Methods Using tumor-derived cell lines from MMTV-Neu mice lacking SLK and biochemical approaches, we have characterized the signaling mechanisms and relevant DNA elements driving Sox10 expression. Results Biochemical and genetic analyses of the SOX10 regulatory region in SLK-deficient mammary tumor cells show that Sox10 expression is dependent on a novel −7kb enhancer that harbors three SoxE binding sites. ChIP analyses demonstrate that Sox9 is bound to those elements in vivo. Our data show that AKT can directly phosphorylate Sox9 in vitro at serine 181 and that AKT inhibition blocks Sox9 phosphorylation and Sox10 expression in SLK(-/-) tumor cells. AKT-mediated Sox9 phosphorylation increases its transcriptional activity on the Sox10 −7kb enhancer without altering its DNA-binding activity. Interestingly, analysis of murine and human mammary tumors reveals a direct correlation between the levels of active phospho-Sox9 S181 and Sox10 expression. Conclusions Our results have identified a novel Sox10 enhancer and validated Sox9 as a direct target for AKT. As Sox10 is a biomarker for triple-negative breast cancers (TNBC), these findings might have major implications in the targeting and treatment of those cancers.

Primary occurrence of Malignant Peripheral Nerve Sheath Tumor (MPNST) in the skin is rare. Superficial primary MPNST with a cutaneous or subcutaneous origin represents a small subset of MPNST thought to be derived from cutaneous neurofibromas or small peripheral nerves Cutaneous MPNST. We report a case of a 36-year-old man with no history of neurofibromatosis presented to the surgical clinic with a swelling and an infection over his Left thumb for six months. Clinically, there was concern over the Panaritium. An excisional biopsy was performed and revealed a Cutaneous MPNST. Tumor composed of malignant epithelioid and spindle cells arising in the dermis and subcutis. The malignant cells were positive for Vimentin, S-100, SOX10, CD99, β-Catenin, CD10, SMA, H3K27me3, P53, They were negative for Desmin, CD34 (-), ERG, Fli1, H-Cald , MyoD1, Myogenin, Pan-mel, TLE1, NF, ALK, HMB45 and MelanA. The Ki-67 labelling index was 40%. Pulmonary metastasis, Pancreatic metastasis, Left Axillary metastasis, and Left Elbow fossa metastasis were confirmed by PET-CT two months after tumor tissue had been excised. Five courses of chemotherapy and radiation have been offered. He remained well with no symptoms or development at five months of follow-up.

Gliomas are the most common type of primary brain tumors. CircRNA ephrin type‐B receptor 4 (circEPHB4) is a circular RNA derived from the receptor tyrosine kinase EPHB4. However, the clinical significance and the specific roles of circEPHB4 in gliomas and glioma cancer stem cells (CSC) have not been studied. Here, we found that circEPHB4 (hsa_circ_0081519) and SOX10 were up‐regulated and microRNA (miR)‐637 was down‐regulated in glioma tissues and cell lines. Consistently, circEPHB4 was positively correlated with SOX10 but negatively correlated with miR‐637. The altered expressions of these molecules were independently associated with overall survival of patients. CircEPHB4 up‐regulated SOX10 and Nestin by directly sponging miR‐637, thereby stimulating stemness, proliferation and glycolysis of glioma cells. Functionally, silencing circEPHB4 or increasing miR‐637 levels in glioma cells was sufficient to inhibit xenograft growth in vivo. In conclusion, the circEPHB4/miR‐637/SOX10/Nestin axis plays a central role in controlling stem properties, self‐renewal and glycolysis of glioma cells and predicts the overall survival of glioma patients. Targeting this axis might provide a therapeutic strategy for malignant gliomas.

Abstract Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly malignant neoplasms posing diagnostic challenge due to a lack of defining molecular markers. CNS neuroblastoma with forkhead box R2 (FOXR2) activation (CNS_NBL) emerged as a distinct pediatric brain tumor entity from a pool previously diagnosed as primitive neuroectodermal tumors of the central nervous system (CNS-PNETs). Current standard of identifying CNS_NBL relies on molecular analysis. We set out to establish immunohistochemical markers allowing safely distinguishing CNS_NBL from morphological mimics. To this aim we analyzed a series of 84 brain tumors institutionally diagnosed as CNS-PNET. As expected, epigenetic analysis revealed different methylation groups corresponding to the (1) CNS-NBL (24%), (2) glioblastoma IDH wild-type subclass H3.3 G34 (26%), (3) glioblastoma IDH wild-type subclass MYCN (21%) and (4) ependymoma with RELA_C11orf95 fusion (29%) entities. Transcriptome analysis of this series revealed a set of differentially expressed genes distinguishing CNS_NBL from its mimics. Based on RNA-sequencing data we established SOX10 and ANKRD55 expression as genes discriminating CNS_NBL from other tumors exhibiting CNS-PNET. Immunohistochemical detection of combined expression of SOX10 and ANKRD55 clearly identifies CNS_NBL discriminating them to other hemispheric CNS neoplasms harboring “PNET-like” microscopic appearance. Owing the rarity of CNS_NBL, a confirmation of the elaborated diagnostic IHC algorithm will be necessary in prospective patient series.

Abstract Background Waardenburg syndrome (WS) is a rare genetic disorder. The purpose of this study was to investigate clinical and molecular characteristics of WS in four probands from four different Iranian families. Case presentation The first patient was a 1-year-old symptomatic boy with congenital hearing loss and heterochromia iridis with a blue segment in his left iris. The second case was a 1.5-year-old symptomatic girl who manifested congenital profound hearing loss, brilliant blue eyes, and skin hypopigmentation on the abdominal region at birth time. The third patient was an 8-month-old symptomatic boy with developmental delay, mild atrophy, hypotonia, brilliant blue eyes, skin hypopigmentation on her hand and foot, Hirschsprung disease, and congenital profound hearing loss; the fourth patient was a 4-year-old symptomatic boy who showed dystopia canthorum, broad nasal root, synophrys, skin hypopigmentation on her hand and abdomen, brilliant blue eyes, and congenital profound hearing loss. Whole exome sequencing (WES) was used for each proband to identify the underlying genetic factor. Sanger sequencing was performed for validation of the identified mutations in probands and the available family members. A novel heterozygous frameshift mutation, c.996delT (p.K334Sfs*15), on exon 8 of the MITF gene was identified in the patient of the first family diagnosed with WS2A. Two novel de novo heterozygous mutations including a missense mutation, c.950G > A (p.R317K), on exon 8 of the MITF gene, and a frameshift mutation, c.684delC (p.E229Sfs*57), on the exon 3 of the SOX10 gene were detected in patients of the second and third families with WS2A and PCWH (Peripheral demyelinating neuropathy, Central dysmyelinating leukodystrophy, Waardenburg syndrome, Hirschsprung disease), respectively. A previously reported heterozygous frameshift mutation, c.1024_1040del AGCACGATTCCTTCCAA, (p.S342Pfs*62), on exon 7 of the PAX3 gene was identified in the patient of the fourth family with WS1. Conclusions An exact description of the mutations responsible for WS provides useful information to explain the molecular cause of clinical features of WS and contributes to better genetic counseling of WS patients and their families.

The COMMD (copper metabolism MURR1 domain containing) family includes ten structurally conserved proteins (COMMD1 to COMMD10) in eukaryotic multicellular organisms that are involved in a diverse array of cellular and physiological processes, including endosomal trafficking, copper homeostasis, and cholesterol metabolism, among others. To understand the role of COMMD10 in embryonic development, we used Commd10Tg(Vav1-icre)A2Kio/J mice, where the Vav1-cre transgene is integrated into an intron of the Commd10 gene, creating a functional knockout of Commd10 in homozygous mice. Breeding heterozygous mice produced no COMMD10-deficient (Commd10Null) offspring, suggesting that COMMD10 is required for embryogenesis. Analysis of Commd10Null embryos demonstrated that they displayed stalled development by embryonic day 8.5 (E8.5). Transcriptome analysis revealed that numerous neural crest-specific gene markers had lower expression in mutant versus wild-type (WT) embryos. Specifically, Commd10Null embryos displayed significantly lower expression levels of a number of transcription factors, including a major regulator of the neural crest, Sox10. Moreover, several cytokines/growth factors involved in early embryonic neurogenesis were also lower in mutant embryos. On the other hand, Commd10Null embryos demonstrated higher expression of genes involved in tissue remodeling and regression processes. Taken together, our findings show that Commd10Null embryos die by day E8.5 due to COMMD10-dependent neural crest failure, revealing a new and critical role for COMMD10 in neural development.

Background: Waardenburg syndrome (WS) is a rare genetic disorder characterized by musculoskeletal abnormalities, deafness and hypopigmentation of hair and skin. This article's aim is to investigate clinical and genetic characteristics of WS in three unrelated Caucasian individuals. Case presentation: The first patient was a 25-year-old female with congenital bilateral hearing loss, bright-blue-eyes, hypopigmentation of hair and skin, megacolon, language retardation, tenosynovitis and neuromas. The second case was an infant symptomatic from birth, with dysphagia, Hirschsprung disease and neurological abnormalities. The third patient was a 14-year-old boy with congenital bilateral hearing loss and ileocolic Hirschsprung disease. In order to identify variants in potentially causal genes of the patients' phenotype, genetical testing was conducted: targeted clinical exome, targeted exome and trio exome, respectively. We identified three novel variants spread throughout the coding sequence of SOX10. The c.395C>G variant identified de novo in patient 1 was a single nucleotide substitution in exon 2. The c.850G>T variant identified as heterozygous in patient 2 was a loss-of-function variant that generated a premature stop codon. The c.966dupT variant identified in patient 3 was a duplication that generated a premature stop codon. It had been identified in his father, arising a possible germinal mosaicism. According to in silico predictors the variant identified in patient 1 was considered as pathogenic, whereas the other two were classified as likely pathogenic. Conclusions: An exact description of the mutations responsible for WS provides useful information to explain clinical features of WS and contributes to better genetic counselling of WS patients. [ABSTRACT FROM AUTHOR]

Leucine‐rich glioma‐inactivated protein 1 (LGI1) is known to play a key role in autosomal dominant lateral temporal lobe epilepsy (ADLTE). The ADLTE is an inherited disease characterized by focal seizures with distinctive auditory or aphasic symptoms. A large number of mutations on the Lgi1 gene have been reported and are believed to be the genetic cause for ADLTE. We identified a novel missense mutation, c.152A>G (p.Asp51Gly), on Lgi1 from a Chinese ADLTE patient who manifests locomotor imbalance and white matter reduction. However, it remains unknown how mutant LGI1 causes white matter abnormalities at molecular and cellular levels. Here, we generated a knock‐in mouse bearing this Lgi1 mutation. We found that Lgi1D51G/D51G mice exhibited impaired defective white matter and motor coordination. We observed that Lgi1D51G/D51G mice displayed a reduced number of mature oligodendrocytes (OLs) and deficient OL differentiation in the white matter. However, the population of oligodendrocyte precursor cells was not affected in Lgi1D51G/D51G mice. Mechanistically, we showed that the Lgi1D51G mutation resulted in altered mTOR signaling and led to decreased levels of Sox10. Given that Sox10 is a key transcriptional factor to control OL differentiation, our results strongly suggest that the Lgi1D51G mutation may cause white matter abnormalities via inhibiting Sox10‐dependent OL differentiation and myelination in the central nervous system. [ABSTRACT FROM AUTHOR]

Neural crest (NC) cells are a dynamic population of embryonic stem cells that create various adult tissues in vertebrate species including craniofacial bone and cartilage and the peripheral and enteric nervous systems. NC development is thought to be a conserved and complex process that is controlled by a tightly-regulated gene regulatory network (GRN) of morphogens, transcription factors, and cell adhesion proteins. While multiple studies have characterized the expression of several GRN factors in single species, a comprehensive protein analysis that directly compares expression across development is lacking. To address this lack in information, we used three closely related avian models, Gallus gallus (chicken), Coturnix japonica (Japanese quail), and Pavo cristatus (Indian peafowl), to compare the localization and timing of four GRN transcription factors, PAX7, SNAI2, SOX9, and SOX10, from the onset of neurulation to migration. While the spatial expression of these factors is largely conserved, we find that quail NC cells express SNAI2, SOX9, and SOX10 proteins at the equivalent of earlier developmental stages than chick and peafowl. In addition, quail NC cells migrate farther and more rapidly than the larger organisms. These data suggest that despite a conservation of NC GRN players, differences in the timing of NC development between species remain a significant frontier to be explored with functional studies. Graphical abstract. Comparative analysis of neural crest (NC) protein spatiotemporal localization in quail, chick, and peafowl embryos. Avian embryos were incubated for different lengths of time to achieve the same developmental stage marked by somite number (somite stage, SS) as described by Hamburger and Hamilton (HH) in 1951. (A) Quail, (B) chick, and (C) peafowl embryos were collected for immunohistochemistry (IHC) to define and quantify the timeline of NC protein expression. We specifically focused on the expression of PAX7, SNAI2, SOX9, and SOX10 proteins. We determined that neural crest development as marked by common NC-specific proteins differs between species. Rather than similar, but scaled development, each organism has its own NC developmental timeline. Quail embryos develop much more rapidly than their counterparts, chick and peafowl. Further, chick and peafowl amino acid sequences are more similar to each other than they are to quail. Animals in figure adapted from BioRender.com. [Display omitted] • Neural crest gene and protein expression appears heterochronous between avians. • Neural crest protein sequences are highly conserved in quail, chick, and peafowl. • Quail neural crest cells migrate out of the neural tube at earlier stages. • Neural crest cells in all three species exhibit heterogeneous populations. • Quail, chick, and peafowl embryos are similar in size at early embryonic stages. [ABSTRACT FROM AUTHOR]

(1) Background: Fine-needle aspiration cytology is often used for the pre-operative diagnosis of melanoma metastases. The diagnosis may not be confidently established based on morphology alone, and immunocytochemistry is mandatory. The choice of the most advantageous immunocytochemical antibodies is critical, as the sample may be scant, and the presence of pigmented histiocytes may be confounding. However, the diagnostic performance of melanocytic markers in this setting is poorly investigated. Moreover, PRAME (preferentially expressed antigen in melanoma) recently emerged as a novel marker for the diagnosis of melanoma. The current work aimed to evaluate the sensitivity and specificity of PRAME for the diagnosis of melanoma metastases in cytological samples, compared to other melanocytic markers. (2) Methods: PRAME, S100, Melan-A, HMB45 and SOX10 were tested on cell block sections of 48 cases of melanoma metastases diagnosed from cytological samples, and 20 cases of reactive lymphadenopathy. (3) Results: S100 and SOX10 showed the highest sensitivity (100%), while the sensitivity of PRAME was 85.4%. PRAME, Melan-A, SOX10 and HMB45 showed a specificity of 100%, while the specificity of S100 was lower (85%), as it marked some histiocytes. (4) Conclusion: PRAME immunocytochemistry is highly specific for the diagnosis of melanoma metastasis from a cytological sample, but is less sensitive compared with other melanocytic markers. [ABSTRACT FROM AUTHOR]

Aims: Basal‐like breast cancer is an aggressive molecular subtype associated with younger age and early relapse. Most cases lack expression of oestrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2, limiting targeted therapeutic options. Basal‐like breast cancer is defined by the expression of genes in the outer/basally located epithelial layer of mammary glands, including those encoding cytokeratin (CK) 5 and CK14, and epidermal growth factor receptor (EGFR). SRY‐box transcription factor 10 (SOX10), for which there is a readily available immunohistochemical stain, is expressed in a subset of breast cancers, particularly triple‐negative carcinomas. In this study, we sought to: (i) assess the association between SOX10 expression and intrinsic molecular subtypes as defined by Prediction Analysis of Microarray 50 (PAM50) gene expression; and (ii) compare the performance of SOX10 with that of other surrogate markers of the basal‐like subtype, including CK5, EGFR, nestin, and inositol polyphosphate 4‐phosphatase type II (INPP4B). Methods and results: SOX10 immunostaining was performed on tissue microarrays constructed from a contemporary series enriched for ER‐negative and weakly ER‐positive cancers that had also undergone PAM50 gene profiling. A total of 211 cases were informative for both SOX10 immunohistochemistry and PAM50 subtype, including 103 basal‐like cancers. Staining for SOX10 was positive in 73 of 103 basal‐like cancers and in only two of 108 cancers of other subtypes (P < 0.001), resulting in a sensitivity of 70.9% and a specificity of 98.1%. SOX10 was more specific than the other tested basal markers, and the results were independent of ER status. Conclusions: SOX10 is a moderately sensitive, but highly specific, immunohistochemical biomarker for the basal‐like intrinsic subtype of breast cancer, which, unlike other commonly used immunohistochemical biomarkers, is independent of hormone receptor status. [ABSTRACT FROM AUTHOR]

SOX10 is important in nonneoplastic oligodendroglial development, but mRNA transcripts and protein expression are identified in a wider variety of CNS glial neoplasms than oligodendrogliomas. We previously demonstrated high levels of SOX10 mRNA and protein in pilocytic astrocytomas (PAs) but not ependymomas (EPNs). We now extend these studies to investigate subsets of these 2 tumors that affect infants, pilomyxoid astrocytomas (PMAs) and infant (

Background/Aim: It can be difficult to establish the origin of a tumor in metastatic breast cancer (MBC), especially with triple-negative breast cancer (TNBC) or high-grade features. We evaluated the diagnostic utility of GATA3, SOX10, and PAX8 panels in MBC by comparing their expression in each molecular subtype of MBC. Patients and Methods: We evaluated 84 MBC and 37 primary TNBC cases using GATA3, SOX10, and PAX8 staining in whole tissue sections. Results: GATA3 was least sensitive in the detection of metastatic TNBC (metastatic non-TNBC, 0.95; metastatic TNBC, 0.37). SOX10 had the lowest overall sensitivity (0.12) but was elevated in metastatic TNBC, even higher than GATA3 (0.59 vs. 0.37). The combination of GATA3, SOX10, and PAX8 expression showed the highest detection rate (MBC, 0.94; metastatic non-TNBC, 0.95; metastatic TNBC, 0.93). Conclusion: We recommend combining GATA3, SOX10, PAX8 expression profiling to confirm breast as the site of origin in metastatic MBC. [ABSTRACT FROM AUTHOR]

Background: Lysophosphatidic acid (LPA) is a pleiotropic lipid messenger that addresses at least six specific G-protein coupled receptors. Accumulating evidence indicates a significant involvement of LPA in immune cell regulation as well as Schwann cell physiology, with potential relevance for the pathophysiology of peripheral neuroinflammation. However, the role of LPA signaling in inflammatory neuropathies has remained completely undefined. Given the broad expression of LPA receptors on both Schwann cells and cells of the innate and adaptive immune system, we hypothesized that inhibition of LPA signaling may ameliorate the course of disease in experimental autoimmune neuritis (EAN).Methods: We induced active EAN by inoculation of myelin protein 2 peptide (P255-78) in female Lewis rats. Animals received the orally available LPA receptor antagonist AM095, specifically targeting the LPA1 receptor subtype. AM095 was administered daily via oral gavage in a therapeutic regimen from 10 until 28 days post-immunization (dpi). Analyses were based on clinical testing, hemogram profiles, immunohistochemistry and morphometric assessment of myelination.Results: Lewis rats treated with AM095 displayed a significant improvement in clinical scores, most notably during the remission phase. Cellular infiltration of sciatic nerve was only discretely affected by AM095. Hemogram profiles indicated no impact on circulating leukocytes. However, sciatic nerve immunohistochemistry revealed a reduction in the number of Schwann cells expressing the dedifferentiation marker Sox2 paralleled by a corresponding increase in differentiating Sox10-positive Schwann cells. In line with this, morphometric analysis of sciatic nerve semi-thin sections identified a significant increase in large-caliber myelinated axons at 28 dpi. Myelin thickness was unaffected by AM095.Conclusion: Thus, LPA1 signaling may present a novel therapeutic target for the treatment of inflammatory neuropathies, potentially affecting regenerative responses in the peripheral nerve by modulating Schwann cell differentiation. [ABSTRACT FROM AUTHOR]

Color patterns within individual feathers are common in birds but little is known about the genetic mechanisms causing such patterns. Here, we investigate the genetic basis for autosomal barring in chicken, a horizontal striping pattern on individual feathers. Using an informative backcross, we demonstrate that the MC1R locus is strongly associated with this phenotype. A deletion at SOX10, underlying the dark brown phenotype on its own, affects the manifestation of the barring pattern. The coding variant L133Q in MC1R is the most likely causal mutation for autosomal barring in this pedigree. Furthermore, a genetic screen across six different breeds showing different patterning phenotypes revealed that the most striking shared characteristics among these breeds were that they all carried the MC1R alleles Birchen or brown. Our data suggest that the presence of activating MC1R mutations enhancing pigment synthesis is an important mechanism underlying pigmentation patterns on individual feathers in chicken. We propose that MC1R and its antagonist ASIP play a critical role for determining within‐feather pigmentation patterns in birds by acting as activator and inhibitor possibly in a Turing reaction–diffusion model. [ABSTRACT FROM AUTHOR]

Abstract Background Peromyscus are the most common mammalian species in North America and are widely used in both laboratory and field studies. The deer mouse, P. maniculatus and the old-field mouse, P. polionotus, are closely related and can generate viable and fertile hybrid offspring. The ability to generate hybrid offspring, coupled with developing genomic resources, enables researchers to conduct linkage analysis studies to identify genomic loci associated with specific traits. Results We used available genomic data to identify DNA polymorphisms between P. maniculatus and P. polionotus and used the polymorphic data to identify the range of genetic complexity that underlies physiological and behavioral differences between the species, including cholesterol metabolism and genes associated with autism. In addition, we used the polymorphic data to conduct a candidate gene linkage analysis for the Dominant spot trait and determined that Dominant spot is linked to a region of chromosome 20 that contains a strong candidate gene, Sox10. During the linkage analysis, we found that the spot size varied quantitively in affected Peromyscus based on genetic background. Conclusions The expanding genomic resources for Peromyscus facilitate their use in linkage analysis studies, enabling the identification of loci associated with specific traits. More specifically, we have linked a coat color spotting phenotype, Dominant spot, with Sox10, a member the neural crest gene regulatory network, and that there are likely two genetic modifiers that interact with Dominant spot. These results establish Peromyscus as a model system for identifying new alleles of the neural crest gene regulatory network.

Abstract Background Multicellular organisms adopt various strategies to tailor gene expression to cellular contexts including the employment of multiple promoters (and the associated transcription start sites (TSSs)) at a single locus that encodes distinct gene isoforms. Schwann cells—the myelinating cells of the peripheral nervous system (PNS)—exhibit a specialized gene expression profile directed by the transcription factor SOX10, which is essential for PNS myelination. SOX10 regulates promoter elements associated with unique TSSs and gene isoforms at several target loci, implicating SOX10-mediated, isoform-specific gene expression in Schwann cell function. Here, we report on genome-wide efforts to identify SOX10-regulated promoters and TSSs in Schwann cells to prioritize genes and isoforms for further study. Results We performed global TSS analyses and mined previously reported ChIP-seq datasets to assess the activity of SOX10-bound promoters in three models: (i) an adult mammalian nerve; (ii) differentiating primary Schwann cells, and (iii) cultured Schwann cells with ablated SOX10 function. We explored specific characteristics of SOX10-dependent TSSs, which provides confidence in defining them as SOX10 targets. Finally, we performed functional studies to validate our findings at four previously unreported SOX10 target loci: ARPC1A, CHN2, DDR1, and GAS7. These findings suggest roles for the associated SOX10-regulated gene products in PNS myelination. Conclusions In sum, we provide comprehensive computational and functional assessments of SOX10-regulated TSS use in Schwann cells. The data presented in this study will stimulate functional studies on the specific mRNA and protein isoforms that SOX10 regulates, which will improve our understanding of myelination in the peripheral nerve.

Hirschsprung disease (HSCR) is complex genetic disorder of the enteric nervous system (ENS) characterized by an absence of ganglion cells in various parts of the intestine. The disease has a strong genetic association with RET-protooncogene (RET) and various genes involved in neural crest development. SOX10 is a transcriptional regulator whose expression is essential in the development of the ENS. The association between single-nucleotide polymorphisms (SNPs) in SOX10, rs139883 and rs139884, and sporadic HSCR has not been reported. We evaluated the genetic associations between two SNPs in SOX10 and Thai sporadic HSCR, using a case-control design. The study included 120 HSCR and 242 sex-matched controls whose DNA was genotyped using the RFLP (rs139883) and Taqman SNP genotyping (rs139884) methods. The study found minor allele frequencies (MAF) at 0.25 and 0.24 for rs139883 (allele C) and rs139884 (allele A), respectively. Both SNPs complied with the Hardy-Weinberg equilibrium and were further examined through disease association. The association analysis found that the risk-genotype of rs139883 (CC) was associated with HSCR (odds ratio [OR] 2.09; 95% confidence interval [CI] 1.07-4.08; P=0.03). When a subgroup analysis was performed, CC genotype of the rs139883 was significantly associated with HSCR only in females (OR 5.6; 95% CI 1.1-19.5; P=0.01). Moreover, the long segment disease group significantly harbored the risk genotype at a higher frequency (28.6%) compared to the short HSCR (12.0%, P=0.02). In conclusion, the study suggests a genetic association between rs139883 in SOX10 and Thai-female HSCR.

Jialin Qi,1,2,* Zhenmin Hu,1,2,* Heng Xiao,3 Ruijie Liu,2 Wei Guo,4 Zhichun Yang,5 Kewen Ma,2 Shitong Su,2 Ping Tang,1 Xunjian Zhou,2 Jianhua Zhou,1,2 Kuansong Wang1,2 1Department of Pathology, School of Basic Medical Science, Central South University, Changsha 410013, People’s Republic of China; 2Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, People’s Republic of China; 3Department of Pathology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, People’s Republic of China; 4Department of Pathology, Hunan Provincial People’s Hospital, Changsha, Hunan 410005, People’s Republic of China; 5Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kuansong Wang; Jianhua Zhou Email 13787146109@126.com; zhoujh15@163.comIntroduction: Differential diagnosis of metaplastic squamous cell carcinoma of breast (MSCCB) is difficult. In particular, in terms of metastatic MSCCB, because of the low speciality of traditional markers such as mammaglobin, gross cystic disease fluid protein-15 (GCDFP-15) and GATA binding protein 3 (GATA3), the most common problem is differentiating the spread of MSCCB to the lung from a primary lung squamous cell carcinoma. It is urgently required to explore a novel marker to aid in differential diagnosis.Aim: The aim of this study is to explore a novel marker to aid in the differential diagnosis of MSCCB from other squamous cell carcinomas (SCC) in other organs.Methods: We tested the expression of SOX10 in 375 human SCC specimens with immunohistochemistry (IHC).Results: In a series of 20 MSCCB, 9 (45%) were positive for SOX10. All of them were triple-negative MSCCB. Conversely, SOX10 was totally negative in another 205 SCC originating from lung, skin, cervix, oral mucosa, and esophagus. In a series of 150 triple-negative breast cancer and their metastatic foci, SOX10 labeling in the primary tumor and metastasis was 78% and 79.3%, respectively, and the agreement rate was 97.3% (P> 0.05).Conclusion: Our findings demonstrate that SOX10 was recommended for differentiating MSCCB from non-mammary metastasis to the breast, as well as for distinguishing primary SCC from metastatic MSCCB, and SOX10 may be valuable in the pathological diagnosis of breast-derived metaplastic squamous cell carcinoma.Keywords: SOX10, squamous cell carcinoma, breast, lung, differential diagnosis

Desmoplastic malignant melanoma is a rare variant of spindle cell melanoma commonly seen in older adults on sun-exposed areas. It accounts for 1–4 % of all cases of cutaneous melanoma. The common location of the desmoplastic melanoma is the head and neck region, whereasother sites are less common. A 45-year-old male presented with an proliferative growth on nose, after a trauma that was diagnosed as tumor. Histopathological examination with the help of wide panel of immunohistochemical methods and with emphasis on SOX10, was, after a broad diferential diagnosis concluded as a desmoplastic melanoma.

In humans, loss of heterozygosity for defective alleles of any of the four subunits of mitochondrial tricarboxylic acid cycle enzyme succinate dehydrogenase (SDH, also Complex II of the electron transport chain) can lead to paraganglioma tumors in neuroendocrine cells. With the goal of developing mouse models of this rare disorder, we have developed various SDH conditional loss strategies. Based on recent lineage tracing studies, we hypothesized that conditional SDHC loss in early embryogenesis during migration of primordial neural crest cells that form the susceptible chromaffin cells of the adrenal medulla might induce paraganglioma. We triggered low levels of detectable SDHC loss in Sox10 + cells at E11.5 of mouse development. We report that, rather than developing adrenal medulla paraganglioma (pheochromocytoma), offspring survived with evidence of neural crest cell dysfunction. Phenotypes included mild lower extremity gait anomalies suggestive of neural tube closure defects and patches of unpigmented fur consistent with neural crest-derived melanocyte dysfunction. These defects were not observed in mice lacking Sdhc knockout. Our results add to existing data suggesting that, unlike humans, even early embryonic (Sox10-driven) SDHx loss is inadequate to trigger paraganglioma in mice of the genetic backgrounds that have been investigated. Instead, low levels of tricarboxylic acid cycle-deficient neural crest cells cause mild developmental defects in hind limb and melanocyte function. This new model may be of interest for studies of metabolism during early neural crest cell development., Competing Interests: The authors report no conflicts of interest., (© 2024 The Authors FASEB BioAdvances published by The Federation of American Societies for Experimental Biology.)

Triple-negative breast cancer (TNBC) refers to an estrogen receptor-negative, progesterone receptor-negative, and HER2-negative breast cancer. Although accepted as a clinically valid category, TNBCs are heterogeneous at the histologic, immunohistochemical, and molecular levels. Gene expression profiling studies have molecularly classified TNBCs into multiple groups, but the prognostic significance is unclear except for a relatively good prognosis for the luminal androgen receptor subtype. Immunohistochemistry (IHC) has been used as a surrogate for basal and luminal subtypes within TNBC, but prognostication of TNBC using IHC is not routinely performed. We aimed to study immunophenotypic correlations in a well-annotated cohort of consecutive TNBCs, excluding postneoadjuvant chemotherapy cases. Tissue microarrays were constructed from a total of 245 TNBC cases. IHC stains were performed and consisted of luminal (AR and INPP4B), basal (SOX10, nestin, CK5, and EGFR), and diagnostic (GCDFP15, mammaglobin, GATA3, and TRPS1) markers. Survival analysis was performed to assess the significance of clinical-pathologic variables including age, histology, grade, lymphovascular invasion, Nottingham prognostic index category, American Joint Committee on Cancer (AJCC) stage, stromal tumor-infiltrating lymphocytes at 10% increment, CD8+ T-cell count, Ki-67 index, PD-L1 status, and chemotherapy along with the results of IHC markers. Apocrine tumors show prominent reactivity for luminal markers and GCDFP15, whereas no special-type carcinomas are often positive for basal markers. TRPS1 is a sensitive marker of breast carcinoma but shows low or no expression in apocrine tumors. High AJCC stage, lack of chemotherapy, and dual SOX10/AR negativity are associated with worse outcomes on both univariable and multivariable analyses. Lymphovascular invasion and higher Nottingham prognostic index category were associated with worse outcomes on univariable but not multivariable analysis. The staining for IHC markers varies based on tumor histology, which may be considered in determining breast origin. Notably, we report that SOX10/AR dual negative status in TNBC is associated with a worse prognosis along with AJCC stage and chemotherapy status., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Oligodendrocytes (OLs) are key players in the central nervous system, critical for the formation and maintenance of the myelin sheaths insulating axons, ensuring efficient neuronal communication. In the last decade, the use of human induced pluripotent stem cells (iPSCs) has become essential for recapitulating and understanding the differentiation and role of OLs in vitro. Current methods include overexpression of transcription factors for rapid OL generation, neglecting the complexity of OL lineage development. Alternatively, growth factor-based protocols offer physiological relevance but struggle with efficiency and cell heterogeneity. To address these issues, we created a novel SOX10-P2A-mOrange iPSC reporter line to track and purify oligodendrocyte precursor cells. Using this reporter cell line, we analyzed an existing differentiation protocol and shed light on the origin of glial cell heterogeneity. Additionally, we have modified the differentiation protocol, toward enhancing reproducibility, efficiency, and terminal maturity. Our approach not only advances OL biology but also holds promise to accelerate research and translational work with iPSC-derived OLs., (© 2024 The Authors. GLIA published by Wiley Periodicals LLC.)

Sox10 is a well known factor to control oligodendrocyte (OL) differentiation, and its expression is regulated by Olig2. As an important protein kinase, Akt has been implicated in diseases with white matter abnormalities. To study whether and how Akt may regulate OL development, we generated OL lineage cell-specific Akt1/Akt2/Akt3 triple conditional knock-out (Akt cTKO) mice. Both male and female mice were used. These mutants exhibit a complete loss of mature OLs and unchanged apoptotic cell death in the CNS. We show that the deletion of Akt three isoforms causes downregulation of Sox10 and decreased levels of phosphorylated FoxO1 in the brain. In vitro analysis reveals that the expression of FoxO1 with mutations on phosphorylation sites for Akt significantly represses the Sox10 promoter activity, suggesting that phosphorylation of FoxO1 by Akt is important for Sox10 expression. We further demonstrate that mutant FoxO1 without Akt phosphorylation epitopes is enriched in the Sox10 promoter. Together, this study identifies a novel FoxO1 phosphorylation-dependent mechanism for Sox10 expression and OL differentiation. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) is a subtype of primary cutaneous T-cell lymphoma (CTCL) with an indolent course that rarely progresses. Histologically, the lesions display a superficial lymphocytic infiltrate with epidermotropism of neoplastic T-cells. Hypopigmented MF is a rare variant that presents with hypopigmented lesions and is more likely to affect young patients. The etiology of the hypopigmentation is unclear. The aim of this study was to assess melanocyte loss in MF through immunohistochemistry (IHC) with SOX10. Twenty cases were evaluated, including seven of the hypopigmented subtype. The neoplastic epidermotropic infiltrate consisted predominantly of CD4+ T-cells in 65% of cases; CD8+ T-cells were present in moderate to abundant numbers in most cases. SOX10 IHC showed a decrease or focal complete loss of melanocytes in 50% of the cases. The predominant neoplastic cell type (CD4+/CD8+), age, race, gender, histologic features, and reported clinical pigmentation of the lesions were not predictive of melanocyte loss. A significant loss of melanocytes was observed in 43% of hypopigmented cases and 54% of conventional cases. Additional studies will increase our understanding of the relationship between observed pigmentation and the loss of melanocytes in MF. [ABSTRACT FROM AUTHOR]

Purpose: Melanoma is a serious and malignant disease worldwide. Seeking diagnostic markers and potential therapeutic targets is urgent for melanoma treatment. SOX10, a member of the SoxE family of genes, is a transcription factor which can regulate the transcription of a wide variety of genes in multiple cellular processes. Methods: The mRNA level and protein expression of SOX10 is confirmed by bioinformatic analysis and IHC staining. MTT, clone formation and EdU analysis showed that SOX10 knockdown (KD) could significantly inhibit melanoma cell proliferation. FACS analysis showed that SOX10 KD could markedly enhance the level of cell apoptosis. The downstream target signaling pathway is predicted by RNA-seq based on the public GEO database. The activation of Notch signaling mediated by SOX10 is tested by qPCR and Western blot. Results: Ectopic upregulation of SOX10 was found in melanoma patient tissues compared to normal nevus tissues in mRNA and protein levels. Furthermore, both mRNA and protein level of SOX10 were negatively correlated with melanoma patient's prognosis. SOX10 knockdown could obviously suppress the proliferation ability of melanoma cells by inactivating Notch signaling pathway. Conclusion: Our study confirmed that SOX10 is an oncogene and activate Notch signaling pathway, which suggests the potential treatment for melanoma patients by target SOX10/Notch axis. [ABSTRACT FROM AUTHOR]