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Purpose: This research aimed to evaluate the expression level of Homeobox A9 (HOXA9) and its role in tumorigenesis of hepatocellular carcinoma (HCC). Methods: Bioinformatic analysis, qPCR and Western blot analysis of clinical samples were employed to evaluate mRNA and protein levels of HOXA9 in HCC patients and cell lines. In vitro cell proliferation, migration and invasion, cloning formation, xenograft tumor model, wound healing and apoptosis assays, RNA sequencing analysis of RPL38-silenced HCC-LM3 cells and qPCR, Western blot analysis were performed for validation. Analysis of HOXA9-related genes were conducted to identify their relationships between HOXA9. Results: HOXA9 is dramatically upregulated in HCC. Upregulation of HOXA9 in HCC predicts poor survival of patients. Besides, HOXA9 promotes proliferation, metastasis and prevents apoptosis in HCC in vitro. In addition, HOXA9 controlled by Ribosomal protein RPL38 is upregulated in HCC. Bioinformatic analysis also indicated that HOXA9 is involved in the regulation of DNA methylation and immune infiltration in HCC. Conclusion: HOXA9 is dramatically upregulated in hepatocellular carcinoma and predicts poor prognosis. Besides, HOXA9 promoted proliferation and metastasis and prevented apoptosis in vitro, which is regulated by Ribosomal protein RPL38 in HCC. [ABSTRACT FROM AUTHOR]

Neural tube defects (NTDs) are a class of major birth defects associated with the central nervous system. With the promotion of folic acid supplementation policy in pregnant women, the incidence of folic acid is decreasing year by year, which makes it difficult to obtain clinical specimens. Therefore, it is particularly important to establish reliable animal models to study the pathogenesis of NTDs. In this study, the NTDs mouse model induced by low folate combined with methotrexate (MTX) and the NTDs mouse model induced by retinoic acid (RA) were respectively established. transcriptome sequencing (RNA-seq) was performed on the brain tissue of NTDs fetal mice and differential expression profiles were analyzed. The results were verified by real-time quantitative polymerase chain reaction (RT-qPCR). The results showed that the incidence of NTDs induced by low folate combined with MTX was 21.7%. RA-induced fetal mice showed strong teratogenicity, with a deformity rate of 73.2%. Compared with normal fetal mice, 1 443 differentially expressed genes (DEGs) were screened in NTDs mice induced by low folate combined with MTX. Totally 3 070 DEGs were screened in RA-induced NTDs mice. Bioinformatics analysis of DEGs showed that the up-regulated genes were mainly involved in the antero-posterior axis development, regionalization, pattern differentiation and other biological processes. KEGG enrichment showed that up-regulated genes were associated with myocardial contraction, cardiomyopathy, and neuroactive ligand-receptor interactions. Veen intersection analysis of DEGs in the two models showed that a total of 132 DEGs were significantly up-regulated in both sets of models, including the Hox gene family. The results were verified by RT-qPCR and found to be consistent with those of RNA-seq. In this study, RNA-seq and differential expression profiles were analyzed in the fetal brains of two NTDs mice, and it was found that the abnormal expression of Hox might lead to the occurrence of NTDs, which provided exploration and reflection for the subsequent pathogenesis research. [ABSTRACT FROM AUTHOR]

Homeobox genes encode transcription factors that are widely known to control developmental processes. This is also the case in the pineal gland, a neuroendocrine brain structure devoted to nighttime synthesis of the hormone melatonin. Thus, in accordance with high prenatal gene expression, knockout studies have identified a specific set of homeobox genes that are essential for development of the pineal gland. However, as a special feature of the pineal gland, homeobox gene expression persists into adulthood, and gene product abundance exhibits 24 h circadian rhythms. Recent lines of evidence show that some homeobox genes even control expression of enzymes catalyzing melatonin synthesis. We here review current knowledge of homeobox genes in the rodent pineal gland and suggest a model for dual functions of homeobox gene‐encoded transcription factors in developmental and circadian mature neuroendocrine function. [ABSTRACT FROM AUTHOR]

Spermatogonial stem cells (SSCs) are essential for male fertility. Here, we report that mouse SSC generation is driven by a transcription factor (TF) cascade controlled by the homeobox protein, RHOX10, which acts by driving the differentiation of SSC precursors called pro-spermatogonia (ProSG). We identify genes regulated by RHOX10 in ProSG in vivo and define direct RHOX10-target genes using several approaches, including a rapid temporal induction assay: iSLAMseq. Together, these approaches identify temporal waves of RHOX10 direct targets, as well as RHOX10 secondary-target genes. Many of the RHOX10-regulated genes encode proteins with known roles in SSCs. Using an in vitro ProSG differentiation assay, we find that RHOX10 promotes mouse ProSG differentiation through a conserved transcriptional cascade involving the key germ-cell TFs DMRT1 and ZBTB16. Our study gives important insights into germ cell development and provides a blueprint for how to define TF cascades.

Abscisic acid (ABA) signalling triggers drought resistance mediated by SNF1‐related kinase 2s (SnRK2s), which transmits stress signals through the phosphorylation of several downstream factors. However, these kinases and their downstream targets remain elusive in pepper plants. This study aimed to isolate interacting partners of CaSnRK2.6, a homologue of Arabidopsis SnRK2.6/OST1. Among the candidate proteins, we identified a homeodomain‐leucine zipper (HD‐Zip) class II protein and named it CaHAT1 (Capsicum annuum homeobox ABA signalling related‐ transcription factor 1). CaHAT1‐silenced pepper and ‐overexpression (OE) transgenic Arabidopsis plants were generated to investigate the in vivo function of CaHAT1 in drought response. Following the application of drought stress, CaHAT1‐silenced pepper plants exhibited drought‐sensitive phenotypes with reduced ABA‐mediated stomatal closure and lower expression of stress‐responsive genes compared with control plants. In contrast, CaHAT1‐OE transgenic Arabidopsis plants showed the opposite phenotypes, including increased drought resistance and ABA sensitivity. CaHAT1, particularly its N‐terminal consensus sequences, was directly phosphorylated by CaSnRK2.6. Furthermore, CaSnRK2.6 kinase activity and CaSnRK2.6‐mediated CaHAT1 phosphorylation levels were enhanced by treatment with ABA and drought stress. Taken together, our results indicated that CaHAT1, which is the target protein of CaSnRK2.6, is a positive regulator of drought stress response. This study advances our understanding of CaHAT1–CaSnRK2.6 mediated defence mechanisms in pepper plants against drought stress. Summary Statement: We previously reported that pepper SnRK2 type kinase CaSnRK2.6 functions as a positive modulator of abscisic acid (ABA) signalling and drought response. Building on this in the present study, we identified the homeodomain‐leucine zipper class II protein CaHAT1 as a substrate of CaSnRK2.6, which plays a positive role in the regulation of drought stress response via ABA‐mediated signalling. [ABSTRACT FROM AUTHOR]

To reveal whether hysteroscopic removal of the International Federation of Gynecology and Obstetrics (FIGO) types 0 and 1 fibroids makes any changes in the expression of homeobox genes (HOXA10 , HOXA11), leukemia inhibitory factor, and nuclear factor-kappa B (NF-kB). A case-control study. University-based in vitro fertilisation center. This study consisted of a total of 29 participants, 21 with FIGO types 0 and 1 fibroids and 8 with normal uterine cavity without fibroids. Patients in FIGO types 0 and 1 fibroids group underwent hysteroscopic myomectomy. The patients in the control group underwent laparoscopic tubal ligation. Endometrial cells were collected by flushing method from all participants before and 3 months after myomectomy. Real-time polymerase chain reaction was used to detect HOXA10, HOXA11, and LIF mRNA expressions in endometrial flushing samples. The relative expressions of homeobox and LIF mRNA were calculated with comparative ΔCt method. Endometrial NF-kB concentration was measured quantitatively by enzyme-linked immunosorbent assay. To compare endometrial HOXA10, HOXA11, and LIF mRNA expressions as well as endometrial NF-kB concentration before and after myomectomy. Premyomectomy NF-kB levels of type 0 (4.22 ± 1.02 ng/mL) and type 1 fibroid (6.44 ± 2.30 ng/mL) were significantly higher than the values of control group (0.54 ± 0.10 ng/mL). Surgical removal of type 0 and 1 fibroids resulted in a significant decrease in endometrial NF-kB levels (1.33 ± 0.02 ng/mL vs 1.65 ± 0.27 ng/mL, respectively). In type 0 fibroid group, after myomectomy, there was a 11.1-fold increase in HOXA10 mRNA, 4.23-fold in HOXA11 mRNA, and 7.63-fold in LIF mRNA. In the type 1 fibroid group, after myomectomy, there was a 16.3-fold increase in HOXA10 mRNA, 8.34-fold in HOXA11 mRNA, and 9.38-fold in LIF mRNA. A nonsignificant change was detected in homeobox and LIF mRNA after tubal sterilization. A negative and significant correlation was found between endometrial NF-kB and HOXA10 (r=-0.67), HOXA11 (r=-0.71) and LIF (r=-0.54). High proinflammatory NF-kB concentration and low homeobox and LIF mRNA expressions were detected in the presence of type 0 or 1 fibroids that returned to normal values after hysteroscopic myomectomy. [ABSTRACT FROM AUTHOR]

Homeobox genes play essential roles in the early development of many animals. Although the repertoire of most homeobox genes, including three amino acid loop extension (TALE)‐type homeobox genes, is conserved in animals, spiralian‐TALE (SPILE) genes are a notable exception. In this study, SPILE genes were extracted from the genomic data of 22 mollusk species and classified into four clades (‐A/C, ‐B, ‐D, and ‐E) to determine which SPILE genes exhibit dynamic repertoire changes. While SPILE‐D and ‐E duplications were rarely observed, SPILE‐B duplication was observed in the bivalve lineage and SPILE‐A/C duplication was observed in multiple clades. Conversely, most or all SPILE genes were lost in cephalopods and in some gastropod lineages. SPILE gene expression patterns were also analyzed in multiple mollusk species using publicly available RNA‐seq data. The majority of SPILE genes examined, particularly those in the A/C‐ and B‐clades, were specifically expressed during early development, suggesting that most SPILE genes exert specific roles in early development. This comprehensive cataloging and characterization revealed a dynamic evolutionary history, including SPILE‐A/C and ‐B gene duplications and the loss of SPILE genes in several lineages. Furthermore, this study provides a useful resource for studying the molecular mechanism of spiralian early development and the evolution of young and lineage‐specific transcription factors. [ABSTRACT FROM AUTHOR]

The caudal type homeobox 2 (CDX2) gene encodes a developmental regulator involved in caudal body patterning. Only three pathogenic variants in human CDX2 have been described, in patients with persistent cloaca, sirenomelia and/or renal and anogenital malformations. We identified five patients with de novo or inherited pathogenic variants in CDX2 with clinical phenotypes that partially overlap with previous cases, that is, imperforate anus and renal, urogenital and limb abnormalities. However, additional clinical features were seen including vertebral agenesis and we describe considerable phenotypic variability, even in unrelated patients with the same recurrent p.(Arg237His) variant. We propose CDX2 variants as rare genetic cause for a multiple congenital anomaly syndrome that can include features of caudal regression syndrome and VACTERL. A causative role is further substantiated by the relationship between CDX2 and other proteins encoded by genes that were previously linked to caudal abnormalities in humans, for example, TBXT (sacral agenesis and other vertebral segmentation defects) and CDX1 (anorectal malformations). Our findings confirm the essential role of CDX2 in caudal morphogenesis and formation of cloacal derivatives in humans, which to date has only been well characterized in animals. [ABSTRACT FROM AUTHOR]

Background DNA damage repair is an important mechanism of platinum resistance. HOXB7 is one member of HOX family genes, which are essential developmental regulators and frequently dysregulated in cancer. Recently, its relevance in chemotherapy resistance and DNA damage repair has also been addressed. However, little is known regarding the association between HOXB7 and chemotherapy resistance in esophageal squamous cell carcinoma (ESCC). Methods The association between HOXB7 expression detected by immunohistochemisty and tumor regression grade (TRG) and long‐term survival was analyzed in 143 ESCC patients who underwent neoadjuvant chemotherapy. CCK8 assay was used to examine the effect of cisplatin in a panel of four ESCC cell lines. A stable cell strain with HOXB7 knockdown of KYSE150 and KYSE450 was established to explore the effect on cisplatin sensitivity. The interaction of HOXB7 with Ku70, Ku80 and DNA‐PKcs was determined by GST‐pull down, coimmunoprecipitation and immunofluorescent colocalization. Finally, we investigated whether disrupting HOXB7 function by a synthetic peptide HXR9 blocking the formation of HOXB7/PBX could enhance cisplatin sensitivity in vitro and in vivo. Results High expression of HOXB7 was associated with cisplatin resistance and worse chemotherapy efficacy. HOXB7 knockdown reinforced cisplatin sensitivity. It was identified that HOXB7 interacts with Ku70, Ku80 and DNA‐PKcs. HOXB7 knockdown was related to the downregulation of Ku70, Ku80 and DNA‐PKcs as well as arrested cell cycle in S phase. HOXB7 inhibition by HXR9 had a synergistic effect to improve cisplatin sensitivity. Conclusion HOXB7 may be a biomarker for the prediction of chemoresistance of ESCC and serves as a promising therapeutic target.

Rax is one of the key transcription factors crucial for vertebrate eye development. In this study, we conducted comprehensive evolutionary analysis of Rax. We found that Bilateria and Cnidaria possess Rax, but Placozoa, Porifera, and Ctenophora do not, implying that the origin of the Rax gene dates back to the common ancestor of Cnidaria and Bilateria. The results of molecular phylogenetic and synteny analyses on Rax loci between jawed and jawless vertebrates indicate that segmental duplication of the Rax locus occurred in an early common ancestor of jawed vertebrates, resulting in two Rax paralogs in jawed vertebrates, Rax and Rax2. By analyzing 86 mammalian genomes from all four major groups of mammals, we found that at least five independent Rax2 gene loss events occurred in mammals. This study may provide novel insights into the evolution of the eye.

Overarching themes in the terminal differentiation of the enteric nervous system, an autonomously acting unit of animal nervous systems, have so far eluded discovery. We describe here the overall regulatory logic of enteric nervous system differentiation of the nematode Caenorhabditis elegans that resides within the foregut (pharynx) of the worm. A C. elegans homolog of the Drosophila Sine oculis homeobox gene, ceh-34, is expressed in all 14 classes of interconnected pharyngeal neurons from their birth throughout their life time, but in no other neuron type of the entire animal. Constitutive and temporally controlled ceh-34 removal shows that ceh-34 is required to initiate and maintain the neuron type-specific terminal differentiation program of all pharyngeal neuron classes, including their circuit assembly. Through additional genetic loss of function analysis, we show that within each pharyngeal neuron class, ceh-34 cooperates with different homeodomain transcription factors to individuate distinct pharyngeal neuron classes. Our analysis underscores the critical role of homeobox genes in neuronal identity specification and links them to the control of neuronal circuit assembly of the enteric nervous system. Together with the pharyngeal nervous system simplicity as well as its specification by a Sine oculis homolog, our findings invite speculations about the early evolution of nervous systems.

Artemia is a crustacean genus belonging to the order Anostraca in the class Branchiopoda and lives in inland hypersaline lakes. Among the genus, A. franciscana is a valuable species as a fish food in the aquaculture industry or as an aquatic model organism for toxicity tests. However, genomic data for A. franciscana remains incomplete. In this study, high-quality genome assembly at the chromosome level of female A. franciscana was conducted by combining various sequencing and assembly technologies. The final A. franciscana assembled genome was 1.27 Gb in length, containing 21 chromosomal scaffolds (>10 Mb). The scaffold N50 was 45.3 Mb, with a complete BUSCO value of 91.0 %, thereby confirming that a high-quality genome was assembled. Gene annotation shows that the A. franciscana genome contained 67.26 % of repetitive sequences, and a total of 26,923 protein-coding genes were predicted. Among the 21 chromosome-scale scaffolds, chromosome 1 was identified as a sex chromosome Z. Additionally, five contigs of putative W chromosome fragments and the candidate sex-determining genes were suggested. Ten homeobox ( Hox ) genes were identified in A. franciscana on the chromosome 14, which were in two subclusters with a large gap. Hox gene organizations within 13 arthropods showed that four anostracans had conserved synteny. This study provides a new female Artemia genome with sex chromosome and the first complete genomic arrangement of the Hox cluster in Anostraca. This study will be a useful genomic and genetic reference for understanding the evolution and development of A. franciscana ., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Whether a gene involved in distinct tissue or cell functions exerts a core of common molecular activities is a relevant topic in evolutionary, developmental, and pathological perspectives. Here, we addressed this question by focusing on the transcription factor and regulator of chromatin accessibility encoded by the Cdx2 homeobox gene that plays important functions during embryonic development and in adult diseases. By integrating RNAseq data in mouse embryogenesis, we unveiled a core set of common genes whose expression is responsive to the CDX2 homeoprotein during trophectoderm formation, posterior body elongation and intestinal specification. ChIPseq data analysis also identified a set of common chromosomal regions targeted by CDX2 at these three developmental steps. The transcriptional core set of genes was then validated with transgenic mouse models of loss or gain of function of Cdx2. Finally, based on human cancer data, we highlight the relevance of these results by displaying a significant number of human orthologous genes to the core set of mouse CDX2-responsive genes exhibiting an altered expression along with CDX2 in human malignancies.

The Coffea arabica HB12 gene (CaHB12), which encodes a transcription factor belonging to the HD-Zip I subfamily, is upregulated under drought, and its constitutive overexpression (35S:CaHB12 OX ) improves the Arabidopsis thaliana tolerance to drought and salinity stresses. Herein, we generated transgenic cotton events constitutively overexpressing the CaHB12 gene, characterized these events based on their increased tolerance to water deficit, and exploited the gene expression level from the CaHB12 network. The segregating events Ev8.29.1, Ev8.90.1, and Ev23.36.1 showed higher photosynthetic yield and higher water use efficiency under severe water deficit and permanent wilting point conditions compared to wild-type plants. Under well-irrigated conditions, these three promising transformed events showed an equivalent level of Abscisic acid (ABA) and decreased Indole-3-acetic acid (IAA) accumulation, and a higher putrescine/(spermidine + spermine) ratio in leaf tissues was found in the progenies of at least two transgenic cotton events compared to non-transgenic plants. In addition, genes that are considered as modulated in the A. thaliana 35S:CaHB12 OX line were also shown to be modulated in several transgenic cotton events maintained under field capacity conditions. The upregulation of GhPP2C and GhSnRK2 in transgenic cotton events maintained under permanent wilting point conditions suggested that CaHB12 might act enhancing the ABA-dependent pathway. All these data confirmed that CaHB12 overexpression improved the tolerance to water deficit, and the transcriptional modulation of genes related to the ABA signaling pathway or downstream genes might enhance the defense responses to drought. The observed decrease in IAA levels indicates that CaHB12 overexpression can prevent leaf abscission in plants under or after stress. Thus, our findings provide new insights on CaHB12 gene and identify several promising cotton events for conducting field trials on water deficit tolerance and agronomic performance. • CaHB12 gene overexpression does not affect ABA hormone accumulation. • CaHB12 gene overexpression reduces IAA hormone accumulation in leaves. • CaHB12 gene overexpression increase putrescine/(spermidine + spermine) ratio in leaf tissues. • CaHB12 ox transgenic events showed a decrease in the IAA levels indicates that CaHB12 gene overexpression can prevent leaf abscission in plants under water deficit stress. • CaHB12 ox transgenic events showed improved tolerance to water deficit. [ABSTRACT FROM AUTHOR]

Objective: To understand the role of MSX1 gene in Pakistani families with hypodontia. Study Design: Descriptive study. Place and Duration of Study: This descriptive study was performed in Human Molecular Genetics (HMG) Laboratory of Baluchistan University of Information Technology, Engineering and Management Sciences (BUITEMS). The study was of 5 months duration. Material and Methods: Peripheral blood sample of 5 ml was extracted intravenously from all affected individuals, normal siblings and their parents in 15ml falcon tubes containing 200μl EDTA. Human genomic DNA was extracted by using inorganic method from the blood leukocytes (samples) following a standardized protocol already established in Human Molecular Genetics (HMG) laboratory of BUITEMS. Two coding exons of MSX1 (NM_002448.3) were amplified and sequenced. Sequence analysis of the coding region of MSX1 gene is reveal through Bio Edit, Chromas and Seqman software’s. Results: Hypodontia of permanent teeth of each affected family member was confirmed from history, clinical and radiographic examination. The clinical examination of Family 1 (proband I) revealed missing maxillary teeth 12, 18, 22, 28 and mandibular teeth 31, 41, 42 (FDI number system). The proband I-1 has also shown dental malformation of teeth and tongue tie. Family 2 (proband II) had missing maxillary lateral incisor 12, 22 (FDI number system). Cephalometric analysis showed that proband I and proband II both had mild skeleton class-II malocclusion (ANB-6º, ANB-5º respectively) with normal vertical pattern. Dental cast analysis showed class-II dental relation with large midline diastema and anterior spaces in both affected proband. The coding region of MSX1 exons were sequenced and analyzed through Bio Edit, Chromas and Seqman software’s and a missense mutation was found. Here the transition of alanine-to-glycine lead to a substitution at amino acid position 40(c.119C>G p. Ala40Gly). Conclusion: This genetic study revealed missense mutation (c.119C>G p.Ala40Gly) in exon 1 of MSX1 gene in Pakistani families with upper lateral hypodontia along with other dental anomalies including microdontia and tongue tie.

Background: DNA damage repair is an important mechanism of platinum resistance. HOXB7 is one member of HOX family genes, which are essential developmental regulators and frequently dysregulated in cancer. Recently, its relevance in chemotherapy resistance and DNA damage repair has also been addressed. However, little is known regarding the association between HOXB7 and chemotherapy resistance in esophageal squamous cell carcinoma (ESCC). Methods: The association between HOXB7 expression detected by immunohistochemisty and tumor regression grade (TRG) and long‐term survival was analyzed in 143 ESCC patients who underwent neoadjuvant chemotherapy. CCK8 assay was used to examine the effect of cisplatin in a panel of four ESCC cell lines. A stable cell strain with HOXB7 knockdown of KYSE150 and KYSE450 was established to explore the effect on cisplatin sensitivity. The interaction of HOXB7 with Ku70, Ku80 and DNA‐PKcs was determined by GST‐pull down, coimmunoprecipitation and immunofluorescent colocalization. Finally, we investigated whether disrupting HOXB7 function by a synthetic peptide HXR9 blocking the formation of HOXB7/PBX could enhance cisplatin sensitivity in vitro and in vivo. Results: High expression of HOXB7 was associated with cisplatin resistance and worse chemotherapy efficacy. HOXB7 knockdown reinforced cisplatin sensitivity. It was identified that HOXB7 interacts with Ku70, Ku80 and DNA‐PKcs. HOXB7 knockdown was related to the downregulation of Ku70, Ku80 and DNA‐PKcs as well as arrested cell cycle in S phase. HOXB7 inhibition by HXR9 had a synergistic effect to improve cisplatin sensitivity. Conclusion: HOXB7 may be a biomarker for the prediction of chemoresistance of ESCC and serves as a promising therapeutic target. [ABSTRACT FROM AUTHOR]

Tooth morphogenesis is regulated by complex interplay between the genetic components. Dlx-1 is a homeobox gene encoding a transcription factor with functions linked to the craniofacial, limb and bone development. The Dlx-1 gene plays a vital role in the initiation of the tooth development process. The rationale of the present study was to elucidate the functional role of Dlx-1 mutations in the development of teeth using the in silico tools. In this study, the list of missense mutations in the Dlx-1 gene was retrieved from Ensembl database. Further, the deleterious effect of missense mutations was assessed using a variety of prediction tools such as SIFT, PolyPhen-2 and PROVEAN. Protein stability analysis and pathogenicity of the predicted variants was carried out using the I-Mutant Suite and MutPred tool respectively. The transcript of Dlx-1 gene analyzed was found to harbour 130 missense mutations. Among these mutations, 12 missense mutations were identified as damaging as assessed by three tools, viz., SIFT, PolyPhen and PROVEAN. Out of 12 damaging variants, 10 were found to decrease the stability of the protein, whereas 2 were found to increase the stability. Further, four variants with decreased stability were categorized as highly pathogenic (>0.800) depending on the MutPred Score. The association between these variants and their role in tooth development was verified using a text-mining process. Pathogenic mutations identified in the Dlx-1 gene provide a novel insight into the genotyping approach which could provide substantial information about the crucial mutations and their association with the developmental process. The mutations identified in the present study should be validated using population based experiments so as to derive an association between the Dlx-1 mutations and disorders related to tooth morphogenesis. [ABSTRACT FROM AUTHOR]

Targeted disruption of the murine Hoxd10 gene (ΔHoxd10) leads to a high frequency of localized (gland-to-gland or regionally within a gland) lactation impairment in homozygous mutant mice as a single gene mutation. The effect of Hoxd10 disruption was enhanced by simultaneous disruption of Hoxd9 (ΔHoxd9/d10), a mutation shown previously to have no effect on mammary function as a single gene alteration. Mammary glands of homozygous ΔHoxd10 and ΔHoxd9/d10 females were indistinguishable from those of wild type littermate and age-matched control mice in late pregnancy. However, in lactation, 47% of homozygous ΔHoxd10 females, and 100% of homozygous ΔHoxd9/d10 females, showed localized or complete failure of two or more glands to undergo lactation-associated morphological changes and to secrete milk. Affected regions of ΔHoxd10 and ΔHoxd9/d10 mutants showed reduced prolactin receptor expression, reduced signal transducer and activator transcription protein 5 (STAT5) phosphorylation, reduced expression of downstream milk proteins, mislocalized glucose transporter 1 (GLUT1), increased STAT3 expression and phosphorylation, recruitment of leukocytes, altered cell cycle status, and increased apoptosis relative to unaffected regions and wild type control glands. Despite these local effects on alveolar function, transplantation results and hormone analysis indicate that Hoxd10 primarily has systemic functions that confer attenuated STAT5 phosphorylation on both wild type and ΔHoxd10 transplants when placed in ΔHoxd10 hosts, thereby exacerbating an underlying propensity for lactation failure in C57Bl/6 mice. [ABSTRACT FROM AUTHOR]

Regeneration of cardiomyocytes, endothelial cells and vascular smooth muscle cells (three major lineages of cardiac tissues) following myocardial infarction is the critical step to recover the function of the damaged heart. Myeloid ecotropic viral integration site 1 (Meis1) was first discovered in leukemic mice in 1995 and its biological function has been extensively studied in leukemia, hematopoiesis, the embryonic pattering of body axis, eye development and various genetic diseases, such as restless leg syndrome. It was found that Meis1 is highly associated with Hox genes and their cofactors to exert its regulatory effects on multiple intracellular signaling pathways. Recently with the advent of bioinformatics, biochemical methods and advanced genetic engineering tools, new function of Meis1 has been found to be involved in the cell cycle regulation of cardiomyocytes and endothelial cells. For example, inhibition of Meis1 expression increases the proliferative capacity of neonatal mouse cardiomyocytes, whereas overexpression of Meis1 results in the reduction in the length of cardiomyocyte proliferative window. Interestingly, downregulation of one of the circular RNAs, which acts downstream of Meis1 in the cardiomyocytes, promotes angiogenesis and restores the myocardial blood supply, thus reinforcing better regeneration of the damaged heart. It appears that Meis1 may play double roles in modulating proliferation and regeneration of cardiomyocytes and endothelial cells post-myocardial infarction. In this review, we propose to summarize the major findings of Meis1 in modulating fetal development and adult abnormalities, especially focusing on the recent discoveries of Meis1 in controlling the fate of cardiomyocytes and endothelial cells. [ABSTRACT FROM AUTHOR]

Rax is one of the key transcription factors crucial for vertebrate eye development. In this study, we conducted comprehensive evolutionary analysis of Rax. We found that Bilateria and Cnidaria possess Rax, but Placozoa, Porifera, and Ctenophora do not, implying that the origin of the Rax gene dates back to the common ancestor of Cnidaria and Bilateria. The results of molecular phylogenetic and synteny analyses on Rax loci between jawed and jawless vertebrates indicate that segmental duplication of the Rax locus occurred in an early common ancestor of jawed vertebrates, resulting in two Rax paralogs in jawed vertebrates, Rax and Rax2. By analyzing 86 mammalian genomes from all four major groups of mammals, we found that at least five independent Rax2 gene loss events occurred in mammals. This study may provide novel insights into the evolution of the eye. [ABSTRACT FROM AUTHOR]

Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole‐exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families, mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasia, often in combination with asplenia. In a further four‐generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2‐3 was detected which cosegregated with the disease in this large family with a LOD (logarithm of the odds) score of 3.3. NKX2‐3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen. [ABSTRACT FROM AUTHOR]

Objective: To understand the role of MSX1 gene in Pakistani families with hypodontia. Study Design: Descriptive study. Place and Duration of Study: This descriptive study was performed in Human Molecular Genetics (HMG) Laboratory of Baluchistan University of Information Technology, Engineering and Management Sciences (BUITEMS). The study was of 5 months duration. Material and Methods: Peripheral blood sample of 5 ml was extracted intravenously from all affected individuals, normal siblings and their parents in 15ml falcon tubes containing 200μl EDTA. Human genomic DNA was extracted by using inorganic method from the blood leukocytes (samples) following a standardized protocol already established in Human Molecular Genetics (HMG) laboratory of BUITEMS. Two coding exons of MSX1 (NM_002448.3) were amplified and sequenced. Sequence analysis of the coding region of MSX1 gene is reveal through Bio Edit, Chromas and Seqman software's. Results: Hypodontia of permanent teeth of each affected family member was confirmed from history, clinical and radiographic examination. The clinical examination of Family 1 (proband I) revealed missing maxillary teeth 12, 18, 22, 28 and mandibular teeth 31, 41, 42 (FDI number system). The proband I-1 has also shown dental malformation of teeth and tongue tie. Family 2 (proband II) had missing maxillary lateral incisor 12, 22 (FDI number system). Cephalometric analysis showed that proband I and proband II both had mild skeleton class-II malocclusion (ANB-6º, ANB-5º respectively) with normal vertical pattern. Dental cast analysis showed class-II dental relation with large midline diastema and anterior spaces in both affected proband. The coding region of MSX1 exons were sequenced and analyzed through Bio Edit, Chromas and Seqman software's and a missense mutation was found. Here the transition of alanine-to-glycine lead to a substitution at amino acid position 40 (c.119C>G p. Ala40Gly). Conclusion: This genetic study revealed missense mutation (c.119C>G p.Ala40Gly) in exon 1 of MSX1 gene in Pakistani families with upper lateral hypodontia along with other dental anomalies including microdontia and tongue tie. [ABSTRACT FROM AUTHOR]

Homeobox (HOX) genes play vital roles in embryonic development and oncogenesis. In humans, there are 39 HOX genes found in four clusters that are located on different chromosomes. The HOX clusters also contain numerous non-protein-coding RNAs, including some lncRNAs. The HOX cluster-embedded lncRNAs (HOX-lncRNAs), most notably, HOTTIP and HOTAIR play a major role in the regulation of their adjacent coding genes. Recently, most HOX-lncRNAs have been shown to impact tumorigenesis and cancer progression. Several HOX-lncRNAs, including HOTTIP, HOXA11-AS, HOTAIRM1, HOXA-AS3, HOXA10-AS, HOTAIR, and HAGLR, are dysregulated in lung cancer. Moreover, their expression levels are correlated with the clinical features of this disease. These HOX-lncRNAs regulate the proliferation, invasion, migration, and chemo-resistance of lung cancer cells through various molecular mechanisms. Although lncRNAs have received much attention lately, the functions of some HOX-lncRNAs in the development of cancer are unclear. Thus, HOX-embedded lncRNAs should be widely investigated in cancer. Here, we review the functions of HOX-lncRNAs in lung cancer. [ABSTRACT FROM AUTHOR]

Summary: Inflorescence architecture is diverse in angiosperms, and is mainly determined by the arrangement of the branches and flowers, known as phyllotaxy. In rice (Oryza sativa), the main inflorescence axis, called the rachis, generates primary branches in a spiral phyllotaxy, and flowers (spikelets) are formed on these branches. Here, we have studied a classical mutant, named verticillate rachis (ri), which produces branches in a partially whorled phyllotaxy. Gene isolation revealed that RI encodes a BELL1‐type homeodomain transcription factor, similar to Arabidopsis PENNYWISE/BELLRINGER/REPLUMLESS, and is expressed in the specific regions within the inflorescence and branch meristems where their descendant meristems would soon initiate. Genetic combination of an ri homozygote and a mutant allele of RI‐LIKE1 (RIL1) (designated ri ril1/+ plant), a close paralog of RI, enhanced the ri inflorescence phenotype, including the abnormalities in branch phyllotaxy and rachis internode patterning. During early inflorescence development, the timing and arrangement of primary branch meristem (pBM) initiation were disturbed in both ri and ri ril1/+ plants. These findings suggest that RI and RIL1 were involved in regulating the phyllotactic pattern of the pBMs to form normal inflorescences. In addition, both RI and RIL1 seem to be involved in meristem maintenance, because the ri ril1 double‐mutant failed to establish or maintain the shoot apical meristem during embryogenesis. Significance Statement: We revealed that two BELL1‐like genes, RI and RIL1, play a crucial role in elaborating inflorescence architecture by regulating the timing and arrangement of primary branch meristem initiation. In addition, we suggest that these genes are also involved in meristem maintenance. [ABSTRACT FROM AUTHOR]

Conidiation capacity and conidial quality are very important for the production and application of mycopesticides. Most filamentous ascomycetous fungi have two distinct patterns of conidiation. Conidiation through microcycle conidiation proceeds to more rapidly achieve a maximum of conidial yield than normal conidiation and hence is of greater merit for exploitation in mass production of fungal insect pathogens, such as Metarhizium acridum. In this study, the mechanism underlying the conidiation pattern shift in M. acridum was explored by characterization of the fungal homeobox gene MaH1. MaH1 was evidently localized to the nuclei of hyphae and transcriptionally expressed at a maximal level when conidiation began. Intriguingly, deletion of MaH1 in M. acridum resulted in a shift of normal conidiation to microcycle conidiation on one-quarter strength Sabouraud's dextrose agar medium, and hence accelerated conidiation and increased conidial yield. In the deletion mutant, moreover, conidia became larger in size and hyphae cells were shorter in length while conidial virulence and stress tolerance were not altered. As revealed by digital gene expression profiling, MaH1 controlled the shift of conidiation patterns by mediating transcription of a set of genes related to hyphal growth, cell differentiation, conidiation, and some important signaling pathways. These findings indicate that MaH1 and its downstream genes can be exploited to increase the conidial yield for more efficient production of mycopesticides. [ABSTRACT FROM AUTHOR]

The relationship between transcription factor homeobox gene (HOX gene) and pediatric congenital clubfoot (CCF) was studied. The CCF group comprised 35 cases of children, and the control group compised 34 cases of children without congenital malformation. The levels of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in the serum of the control and CCF groups were measured using iNOS and NO kits. Interleukin-1β (IL-1β), IL-6 and tumor necrosis factor-α (TNF-α) related to inflammation in the tissues of both groups were detected by reverse transcription-polymerase chain reaction (RT-PCR). Fatty acid synthase (Fas), Fas ligand (FasL) and Bcl-2-associated X (Bax) related to apoptosis as well as the expression of HOX mRNA, the expression of HOX in the control and CCF groups was detected by western blot analysis, and the differential expression of HOX in the control and CCF groups was statistically analyzed. Results of the kit detection showed that the expression of iNOS and NO in the CCF group were significantly higher than those in the control group, indicating that severe oxidative damage occurred in the CCF group. The results of detecting inflammatory factors and apoptosis by RT-PCR showed that the expression of IL-1β, IL-6, TNF-α, Fas, FasL and Bax mRNA in the CCF group was significantly higher than that in the control group, indicating pathogenesis of CCF was related to inflammation and apoptosis. RT-PCR and western blot analysis revealed HOX was highly expressed in the tissues of CCF, and the expression quantity was significantly stronger than that in the control group. The result of analysis of variance showed that the expression differences of HOX in normal and CCF tissues were statistically significant (P<0.01). Abnormal expression of HOX was closely related to the occurrence and development of CCF, indicating that HOX has important research value in CCF and this functional mechanism is related to oxidative damage, inflammation and apoptosis. Expression of HOX therefore shows promise as an indicator of CCF diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs) are a prospective cell source for tissue regeneration due to their self-renewal abilities and potential to differentiate into different cell lineages, but the molecular mechanisms of the directed differentiation and proliferation are still unknown. Recently, multiple studies have indicated the crucial role of HOX genes in MSC differentiation and proliferation. However, the role of HOXA5 in MSCs remains unknown. Here, we investigated HOXA5 function in stem cells from the apical papilla (SCAPs). After HOXA5 depletion, the results showed a significant decrease in ALP activity and a weakened mineralization ability of SCAPs. The real-time RT-PCR results showed prominently lessened expression of OPN and BSP. The CCK8 and CFSE results displayed inhibited proliferation of SCAPs, and flow cytometry assays revealed arrested cell cycle progression at the S phase. Furthermore, we found that depletion of HOXA5 upregulated p16INK4A and p18INK4C and downregulated the Cyclin A. Our research demonstrated that depletion of HOXA5 inhibited osteogenic differentiation and repressed cell proliferation by arresting cell cycle progression at the S phase via p16INK4A, p18INK4C, and Cyclin A in SCAPs, indicating that HOXA5 has a significant role in maintaining the proliferation and differentiation potential of dental-tissue-derived MSCs. [ABSTRACT FROM AUTHOR]

Homeobox D10 (HOXD10) is a transcription factor from the homeobox gene family that controls cell differentiation and morphogenesis throughout development.Due to their functional interaction, changes in HOXD10 gene expression might induce tumors. This narrative review focuses on how and why the dysregulation in the signaling pathways linked with HOXD10 contributes to the metastatic development of cancer. Organ development and tissue homeostasis need highly conserved homeotic transcription factors from homeobox (HOX) genes. Their dysregulation disrupts regulatory molecule action, causing tumors. The HOXD10 gene is upregulated in breast, gastric, hepatocellular, colorectal, bladder, cholangiocellular carcinoma and prostate cancer. Tumor signaling pathways are affected by HOXD10 gene expression changes. This study examines HOXD10-associated signaling pathway dysregulation, which may alter metastatic cancer signaling. In addition, the theoretical foundations that alter HOXD10-mediated therapeutic resistance in malignancies has been presented. New cancer therapy methods will be simpler to develop with the newly discovered knowledge. This review showed that HOXD10 may be a tumor suppressor gene and a new cancer treatment target signaling pathway. [ABSTRACT FROM AUTHOR]

How genetically regulated growth shapes organ form is a key problem in developmental biology. Here, we investigate this problem using the leaflet-bearing complex leaves of Cardamine hirsuta as a model. Leaflet development requires the action of two growth-repressing transcription factors: REDUCED COMPLEXITY (RCO), a homeodomain protein, and CUP-SHAPED COTYLEDON2 (CUC2), a NAC-domain protein. However, how their respective growth-repressive actions are integrated in space and time to generate complex leaf forms remains unknown. By using live imaging, we show that CUC2 and RCO are expressed in an interspersed fashion along the leaf margin, creating a distinctive striped pattern. We find that this pattern is functionally important because forcing RCO expression in the CUC2 domain disrupts auxin-based marginal patterning and can abolish leaflet formation. By combining genetic perturbations with time-lapse imaging and cellular growth quantifications, we provide evidence that RCO -mediated growth repression occurs after auxin-based leaflet patterning and in association with the repression of cell proliferation. Additionally, through the use of genetic mosaics, we show that RCO is sufficient to repress both cellular growth and proliferation in a cell-autonomous manner. This mechanism of growth repression is different to that of CUC2 , which occurs in proliferating cells. Our findings clarify how the two growth repressors RCO and CUC2 coordinate to subdivide developing leaf primordia into distinct leaflets and generate the complex leaf form. They also indicate different relationships between growth repression and cell proliferation in the patterning and post-patterning stages of organogenesis. [Display omitted] • CUC2 and RCO are expressed in an interspersed pattern in C. hirsuta complex leaves • This interspersed expression is required for complex leaf development • RCO limits both cell proliferation and cellular growth in a cell-autonomous manner • The cellular parameters for growth repression by CUC2 and RCO are distinct Bhatia et al. use time-lapse imaging, genetic perturbations, and cellular growth analysis to show that spatially separated growth-repressive activities of CUC2 and RCO shape C. hirsuta complex leaf form. They find different relationships between cell proliferation and growth repression during patterning and post-patterning stages of organogenesis. [ABSTRACT FROM AUTHOR]

While 20–30% of colorectal cancers (CRCs) may arise from precursors with serrated glands, only 8–10% of CRCs manifest serrated morphology at diagnosis. Markers for distinguishing CRCs arising from ‘serrated’ versus ‘conventional adenoma’ precursors are lacking. We studied 36 human serrated CRCs and found CDX2 loss or BRAF mutations in ~60% of cases and often together (p=0.04). CDX2Null/BRAFV600E expression in adult mouse intestinal epithelium led to serrated morphology tumors (including carcinomas) and BRAFV600E potently interacted with CDX2 silencing to alter gene expression. Like human serrated lesions, CDX2Null/BRAFV600E-mutant epithelium expressed gastric markers. Organoids from CDX2Null/BRAFV600E–mutant colon epithelium showed serrated features, and partially recapitulated the gene expression pattern in mouse colon tissues. We present a novel mouse tumor model based on signature defects seen in many human serrated CRCs – CDX2 loss and BRAFV600E. The mouse intestinal tumors show significant phenotypic similarities to human serrated CRCs and inform about serrated CRC pathogenesis.