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Teaching point: Clival chordoma is a rare find in children, presenting as a locally destructive, T2 hyperintense, and strongly enhancing mass.

This paper highlights the management of 5 patients affected by symptomatic ecchordosis physaliphora (EP), treated via endoscopic endonasal transsphenoidal-transclival approach and contextual multilayer skull base reconstruction. A detailed analysis of each case is provided, along with the review of the current body of literature. A retrospective review of patients treated by means of endoscopic endonasal approach for EP from 2010 to 2020 in the Otolaryngology and Neurosurgery Departments of a tertiary-care referral center for endoscopic skull base surgery was analyzed. Only adult patients with a definitive histopathological and immunohistochemical diagnosis of EP were included in the study. A systematic literature review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed for EP. Five cases of EP were retrieved and included in the study. Four patients presented with CSF leakage: in two cases after minor head trauma, in one case with associated bacterial meningitis, and in one case as only referred symptom. One patient complained diplopia due to VI cranial nerve palsy. No complications or recurrences of the disease were observed after a median follow-up of 37.2 months (range, 18–72 months). A total of 27 studies were identified with the systematic literature review, encompassing 30 patients affected by symptomatic EP who were addressed to surgical treatment. Twenty-five patients underwent complete surgical removal of the EP, while in 5 cases, only subtotal resection was performed. EP might result in a “locus minoris resistentiae” of the skull base, predisposing, in rare cases, to CSF leakage and meningitis, spontaneously or after minor trauma. In cases of symptomatic EP, endoscopic endonasal transsphenoidal-transclival approach represents a safe and effective technique for both EP resection and contextual skull base reconstruction.

Summary Loss of SMARCB1 protein expression has recently been identified in a variety of tumor types such as poorly differentiated chordoma (PCh) and malignant rhabdoid tumor (MRT) including atypical teratoid/rhabdoid tumor (AT/RT). PCh is characterized by poorly differentiated epithelioid tumor cells, sheet arrangement, and coexpression of nonepithelial and epithelial markers. Rhabdoid cells are sometimes present. Therefore, the differentiation of these tumors is often difficult. Brachyury is a transcription factor within the T-box family typically expressed in notochord tissue and chordomas. Some studies have reported high specificity and sensitivity of brachyury expression in chordomas. In the present study, we analyzed immunohistochemical brachyury expression in SMARCB1-deficient tumors and discuss important clinicopathological and diagnostic points, especially in cases of intracranial SMARCB1-deficient tumors with brachyury expression. Brachyury and cytokeratin immunoexpression status was examined in 42 formalin-fixed paraffin-embedded SMARCB1-deficient tumor specimens (PCh, 6 cases; extra-central nervous system [CNS] MRT, 26 cases; AT/RT, 10 cases) and 25 cases of conventional chordoma (CCh). All cases of PCh and CCh showed diffuse immunopositivities for cytokeratin 8, pan-cytokeratin, and brachyury. Brachyury immunoexpression was present in 2 extra-CNS MRT (8%) and 5 AT/RT (50%) cases, but immunopositivity was focal not diffuse. Indeed, in almost all cases of AT/RT (cytokeratin 8, 7/10 cases; pan-cytokeratin, 7/10 cases) and extra-CNS MRT (cytokeratin 8, 23/26 cases; pan-cytokeratin, 25/26 cases), fewer than 50% of cells showed immunoreactivity. Although the histological and clinical features of PCh resemble those of AT/RT, semiquantitative evaluations of the degree of brachyury and cytokeratin immunoexpressivity may help to distinguish PCh from AT/RT.

The notochord is a defining feature of the chordates. The transcription factor Brachyury (Bra) is a key regulator of notochord fate but here we show that it is not a unitary master regulator in the model chordate Ciona. Ectopic Bra expression only partially reprograms other cell types to a notochord-like transcriptional profile and a subset of notochord-enriched genes is unaffected by CRISPR Bra disruption. We identify Foxa.a and Mnx as potential co-regulators, and find that combinatorial cocktails are more effective at reprogramming other cell types than Bra alone. We reassess the network relationships between Bra, Foxa.a and other components of the notochord gene regulatory network, and find that Foxa.a expression in the notochord is regulated by vegetal FGF signaling. It is a direct activator of Bra expression and has a binding motif that is significantly enriched in the regulatory regions of notochord-enriched genes. These and other results indicate that Bra and Foxa.a act together in a regulatory network dominated by positive feed-forward interactions, with neither being a classically defined master regulator.

Background Explanted tissues from vertebrate embryos reliably develop in culture and have provided essential paradigms for understanding embryogenesis, from early embryological investigations of induction, to the extensive study of Xenopus animal caps, to the current studies of mammalian gastruloids. Cultured explants of the Xenopus dorsal marginal zone ("Keller" explants) serve as a central paradigm for studies of convergent extension cell movements, yet we know little about the global patterns of gene expression in these explants. Results In an effort to more thoroughly develop this important model system, we provide here a time-resolved bulk transcriptome for developing Keller explants. Conclusions The dataset reported here provides a useful resource for those using Keller explants for studies of morphogenesis and provide genome-scale insights into the temporal patterns of gene expression in an important tissue when explanted and grown in culture.

How force generated by the morphogenesis of one tissue impacts the morphogenesis of other tissues to achieve an elongated embryo axis is not well understood. The notochord runs along the length of the somitic compartment and is flanked on either side by somites. Vacuolating notochord cells undergo a constrained expansion, increasing notochord internal pressure and driving its elongation and stiffening. Therefore, the notochord is appropriately positioned to play a role in mechanically elongating the somitic compartment. We used multi-photon cell ablation to remove specific regions of the zebrafish notochord and quantify the impact on axis elongation. We show that anterior expansion generates a force that displaces notochord cells posteriorly relative to adjacent axial tissues, contributing to the elongation of segmented tissue during post-tailbud stages. Unexpanded cells derived from progenitors at the posterior end of the notochord provide resistance to anterior notochord cell expansion, allowing for stress generation along the anterior-posterior axis. Therefore, notochord cell expansion beginning in the anterior, and addition of cells to the posterior notochord, act as temporally coordinated morphogenetic events that shape the zebrafish embryo anterior-posterior axis., Summary: Targeted multi-photon tissue ablation reveals that coordinated cell expansion and addition to the notochord in zebrafish embryos contributes to the elongation of segmented tissue required for embryo anterior-posterior axis extension.

Programmed cell senescence is a cellular process that seems to contribute to morphogenesis during embryo development, in addition to cell proliferation, migration, differentiation and programmed cell death, and has been observed in evolutionary distant organisms like mammals, amphibians and fish. Programmed cell senescence is a phenotype similar to stress-induced cellular senescence, characterized by the expression of cell cycle inhibitors such as CDKN1A/p21, increased activity of a lysosomal enzyme with beta-galactosidase activity (coined senescence-associated beta-galactosidase) and, most importantly, secretion of growth factors, interleukins, chemokines, metalloproteases, etc., collectively known as a senescent-associated secretory phenotype that instructs surrounding tissue. How wide is the distribution of programmed cell senescence during mouse development and its specific mechanisms to shape the embryo are still poorly understood. Here, we investigated whether markers of programmed cell senescence are found in the developing mouse spinal cord and notochord. We found discrete areas and developmental windows with high senescence-associated beta galactosidase in both spinal cord and notochord; expression of CDKN1A/p21 was documented in epithelial cells of the spinal cord and the notochord. Treatment of mice embryos developed ex-utero in the presence of the senolytic ABT-263 resulted in decrease senescence-associated beta-galactosidase activity and number of motoneurons. Our data suggest that several cell types undergo programmed cell senescence in developing spinal cord and notochord contributing to morphogenesis.Contribution to the Field StatementCellular senescence is a state in which cells no longer divide but have the remarkable ability to secrete signaling molecules that alter the tissue where they reside. In adults, this state is typically induced by stress situations that cause DNA damage so cells with altered genome do not multiply. Senescent cells also form when a tissue is injured; they help to regenerate damaged tissue and contribute to wound healing. Phagocytic cells eliminate them when their function is done, having a transient existence. During vertebrate development some cells acquire a very similar phenotype, coined programmed cell senescence, and interestingly they have been found in regions that organize the pattern of development of some organs. How wide is the distribution of programmed cell senescence during development and how they help to shape the embryo are still poorly understood. We discovered in mice embryos different types of cells with senescent features located in particular regions of the developing nervous system: where motoneurons form and in a region that secrete molecules that instruct the embryo where different types of neurons will be created. We propose that programed cell senescence contributes to the morphogenesis of the nervous system.

During development the embryo body progressively elongates from head-to-tail along the anterior-posterior (AP) axis. Multiple tissues contribute to this elongation through a combination of convergence and extension and/or volumetric growth. How force generated by the morphogenesis of one tissue impacts the morphogenesis of other axial tissues to achieve an elongated axis is not well understood. The notochord, a rod-shaped tissue possessed by all vertebrates, runs across the entire length of the somitic compartment and is flanked on either side by the developing somites in the segmented region of the axis and presomitic mesoderm in the posterior. Cells in the notochord undergo an expansion that is constrained by a stiff sheath of extracellular matrix, that increases the internal pressure in the notochord allowing it to straighten and elongate. Therefore, it is appropriately positioned to play a role in mechanically elongating the somitic compartment. Here, we use multi-photon mediated cell ablation to remove specific regions of the developing notochord and quantify the impact on axis elongation. We show that anterior notochord cell expansion generates a force that displaces notochord cells posteriorly relative to adjacent axial tissues and contributes to the elongation of segmented tissue during post-tailbud stages of development. Crucially, unexpanded cells derived from progenitors at the posterior end of the notochord provide resistance to anterior notochord cell expansion, allowing for force generation across the AP axis. Therefore, notochord cell expansion beginning in the anterior, and addition of cells to the posterior notochord, act as temporally coordinated morphogenetic events that shape the zebrafish embryo AP axis.

The notochord functions primarily as a supporting tissue to maintain the anteroposterior axis of primitive chordates, a function that is replaced entirely by the vertebral column in many vertebrates. The notochord still appears during vertebrate embryogenesis and plays a crucial role in the developmental pattern formation of surrounding structures, such as the somites and neural tube, providing the basis for the vertebrate body plan. The indispensable role of the notochord has often been referred to as the developmental burden and used to explain the evolutionary conservation of notochord; however, the existence of this burden has not been successfully exemplified so far. Since the adaptive value of target tissues appears to result in the evolutionary conservation of upstream structures through the developmental burden, we performed comparative gene expression profiling of the notochord, somites, and neural tube during the mid-embryonic stages in turtles and chicken to measure their evolutionary conservation. When compared with the somites and neural tube, overall gene expression profiles in the notochord showed significantly lower or merely comparable levels of conservation. However, genes involved in inductive signalings, such as the sonic hedgehog (Shh) cascade and the formation of functional primary cilia, showed relatively higher levels of conservation in all the three structures analyzed. Collectively, these results suggest that shh signals are critical as the inductive source and receiving structures, possibly constituting the inter-dependencies of developmental burden.

SLC7A5 is a transmembrane protein involved in transport of bioactive molecules, such as essential amino acids, l -DOPA, and thyroid hormone. SLC7A5 is detected in the adult brain: the blood–brain barrier (BBB), neurons, and astrocytes. SLC7A5 at the BBB regulates the amount of essential amino acids in the brain, and dysfunction of SLC7A5 leads to autism spectrum disorder. Recently, the expression and the function of slc7a5 during early development are analyzed in Xenopus laevis. Xenopus slc7a5 expresses in the notochord, the inducer of neural tissues, and the eye. Perturbation of slc7a5 expression leads to defects in neural tube closure, primary neurogenesis, and eye formation. It is likely that these defects in neural development are independent of its transport function. Thus, SLC7A5 and possibly other amino acid transporters may have distinct developmental roles in the developing brain while they serve as important amino acid transporters in the adult brain.

The Activator Protein-1 transcription factor family (AP-1) transcriptional complex is historically defined as an early response group of transcription factors formed by dimeric complexes of the Jun, Fos, Atf, and Maf bZIP proteins that control cell proliferation and differentiation by regulating gene expression. It has been greatly investigated in many model organisms across metazoan evolution. Nevertheless, its complexity and variability of action made its multiple functions difficult to be defined. Here, we place the foundations for understanding the complexity of AP-1 transcriptional members in tunicates. We investigated the gene members of this family in the ascidian Ciona robusta and identified single copies of Jun, Fos, Atf3, Atf2/7, and Maf bZIP-related factors that could have a role in the formation of the AP-1 complex. We highlight that mesenchyme is a common cellular population where all these factors are expressed during embryonic development, and that, moreover, Fos shows a wider pattern of expression including also notochord and neural cells. By ectopic expression in transgenic embryos of Jun and Fos genes alone or in combination, we investigated the phenotypic alterations induced by these factors and highlighted a degree of functional conservation of the AP-1 complex between Ciona and vertebrates. The lack of gene redundancy and the first pieces of evidence of conserved functions in the control of cell movements and structural organization exerted by these factors open the way for using Ciona as a helpful model system to uncover the multiple potentialities of this highly complex family of bZIP transcription factors.

This chapter introduces the progress of cell therapies targeting symptomatic intervertebral disc degeneration. It starts by presenting the anatomy of intervertebral discs and the pathology of disc degeneration and chronic low back pain, by which it explains the clinical significance of transplanting therapeutic notochordal and mature nucleus pulposus cells in treating disc degeneration. It then explains the developmental origins of the disc cells, in which the molecular signals that drive the commitment of pluripotent stem cells toward the notochordal lineage are discussed. Further it introduces novel approaches to control the notochordal differentiation of pluripotent stem cells. The molecular and cellular characteristics of the derived notochordal-like cells and their potential therapeutic effects including nucleus pulposus regeneration, paracrine activity, and antiinflammation are discussed. A further discussion of safety for the cells is included to highlight the importance of safety control in the therapeutic development of the pluripotent stem cells–derived therapeutics.

Chordomas are rare malignancies belonging to a family of lesions derived from the primitive notochord. This family includes both benign notochordal cell tumors (BNCTs), e.g., giant vertebral notochordal rest tumors, eccordosis physaliphora, and the various subtypes of chordoma (classic, chondroid, and undifferentiated). Similarities in the imaging characteristic of these lesions may lead them to occasionally be completed with other neoplastic or infectious processes. Hence, the image-guided biopsy is necessary for definitive diagnosis. The conjunction of radiographic and histologic features allows for the differentiation of benign and malignant notochordal neoplasms from one another and from other entities in the differential. Additionally, thorough radiographic evaluation with magnetic resonance imaging, high-resolution computed tomography, and nuclear medicine or other staging scans enhances treatment planning. Using anatomic sequences, diagnostic radiologists can assist their surgical and radiation oncology colleagues in defining tumor boundaries, assessing the involvement of adjacent structures, and ultimately determining the feasibility of en bloc resection. In the future, immunohistological staining and gene sequencing may also facilitate the development of individualized therapies for those with disseminated disease at the time of diagnosis.

Chordomas are locally aggressive, slow-growing tumors. Typically found in the axial skeleton, they are thought to be derived from notochord remnants. The notochord is a critical midline structure present in the early weeks of embryogenesis, where it plays a critical role in left-right and local tissue development. While the nucleus pulposus of the intervertebral disk appears to be derived from the primitive notochord, remnant notochordal cells can be found throughout adult vertebrae. What drives the transition from remnant notochord cell to chordoma remains elusive, and is likely multifactorial, but the expression of the brachyury gene appears central to this process. While wide resection remains the gold standard when possible (with or without radiation), these difficult-to-treat tumors have a high local recurrence rate even when appropriate margins appeared to have been achieved. By better understanding the role of the notochord and notochordal morphogenesis in the origins of chordomas, more efficacious, targeted therapies are currently being developed.

Epidermal growth factor-like domain multiple 6 (Egfl6) is a basement membrane protein and plays an important role in hair follicle morphogenesis, angiogenesis, notochord development in vertebrates. Although egfl6 expression in the developing head was observed in zebrafish, its role for craniofacial development and the determination of the pharyngeal region expressing egfl6, have not been reported yet. Here, we report the expression patterns and function of egfl6 in craniofacial development in zebrafish. egfl6 was expressed sequentially in the developing pharyngeal pouches that are key epithelial structures governing the development of the vertebrate head. However, loss-of-function mutations in egfl6 did not cause any craniofacial defects, including the pouches as well as the thymus and facial cartilages whose development is contingent upon appropriate pouch formation. egfl6 was unlikely redundant with egfl7 expressed in a distinct pharyngeal region from that of egfl6 in craniofacial development because reduction of egfl7 with a MO in egfl6 mutants did not affect craniofacial development. In addition, we found that egfl6 carried an endogenous start loss mutation in the wild-type T��bingen strain, implying egfl6 would be a non-functional gene. Taken all together, we suggest that egfl6 expression in the pharyngeal pouches is not required for craniofacial development in zebrafish.

Marsupial frogs (Hemiphractidae) evolved exceptional mechanisms for the conquest of terrestrial life. These adaptations include very large eggs. In some species eggs reach 10 mm in diameter, and are considered to be the largest in frogs. Females have reproductive modifications for the incubation of embryos in their bodies. Modifications of embryos include adaptations for development inside the body of the mother, and changes in the developmental pattern. Moreover, in some species, oocytes are multinucleated instead of having a single germinal vesicle as in most vertebrates. This chapter provides an overview of the adaptations of marsupial frogs associated with terrestrial life, with a discussion of gastrulation and multinucleated oogenesis.

Cranial base is initially developed at the early embryo. It firstly appears as the anterior notochord cartilage, then it grows to the bilateral and the anterior to constitute the rudimental cartilage cranial base; then several gasified centers appear in the cartilage, gradually extend and interconnect to constitute the cranial base bone. The cranial base is cartilaginous osteogenesis and the other cranial part is intramembranous ossification, which is firstly differentiated into the fibrous membrane from the mesenchyme, secondly one or multiple gasified centers appear in the post-membrane and then they unify into the cranium.

Funding: HE was supported by the Centre National de la Recherche Scientifique and Agence Nationale de la Recherche (ANR) grants nos. ANR-16-CE12-0008-01 and ANR-19-CE13-0011. JG-F was supported by BFU2017-861152-P and PID2020-117820GB-100 grants from the Ministerio de Ciencia y Innovación (Spain). This study was in part supported by the European community through a Marie Curie fellowship (FP7-People-IEF-2008, Project 236867) to IMLS. This research was funded in part by the Wellcome Trust grant ISSF3 (grant number 204821/Z/16/Z) to IMLS. c-Jun N-terminal kinase (JNK) is a multi-functional protein involved in a diverse array of context-dependent processes, including apoptosis, cell cycle regulation, adhesion, and differentiation. It is integral to several signalling cascades, notably downstream of non-canonical Wnt and mitogen activated protein kinase (MAPK) signalling pathways. As such, it is a key regulator of cellular behaviour and patterning during embryonic development across the animal kingdom. The cephalochordate amphioxus is an invertebrate chordate model system straddling the invertebrate to vertebrate transition and is thus ideally suited for comparative studies of morphogenesis. However, next to nothing is known about JNK signalling or cellular processes in this lineage. Pharmacological inhibition of JNK signalling using SP600125 during embryonic development arrests gastrula invagination and causes convergence extension-like defects in axial elongation, particularly of the notochord. Pharynx formation and anterior oral mesoderm derivatives like the preoral pit are also affected. This is accompanied by tissue-specific transcriptional changes, including reduced expression of six3/6 and wnt2 in the notochord, and ectopic wnt11 in neurulating embryos treated at late gastrula stages. Cellular delamination results in accumulation of cells in the gut cavity and a dorsal fin-like protrusion, followed by secondary Caspase-3-mediated apoptosis of polarity-deficient cells, a phenotype only partly rescued by co-culture with the pan-Caspase inhibitor Z-VAD-fmk. Ectopic activation of extracellular signal regulated kinase (ERK) signalling in the neighbours of extruded notochord and neural cells, possibly due to altered adhesive and tensile properties, as well as defects in cellular migration, may explain some phenotypes caused by JNK inhibition. Overall, this study supports conserved functions of JNK signalling in mediating the complex balance between cell survival, apoptosis, differentiation, and cell fate specification during cephalochordate morphogenesis. Publisher PDF

Background/Introduction: Skeletal deformities in teleost fish have already been extensively described in studies on Atlantic salmon and zebrafish. Nevertheless, a toolset encompassing thorough identification and description of vertebral column deformities to study zebrafish models for human diseases with skeletal involvement is currently lacking. Purpose: A detailed characterization of skeletal deformities by identifying, describing and quantifying the anomalies will facilitate the development of a reliable deep-phenotyping tool. This tool can be used to establish data matrices by scoring anomalies present in different zebrafish models, which can be used to quantitatively distinguish mild and severe phenotypes. The ability to determine phenotypic severity in disease models is extremely valuable for proper translation towards human diseases, but also to reveal candidate modifier genes that contribute to intrafamilial skeletal variability. Methods: Zebrafish, 13 col1a1amh13/+, 13 col1a1adc124/+, 11 col1a2mh15/+ and 27 WT siblings, were fixed, and made translucent with a mixture of 4% formalin, Triton X-100 and potassium hydroxide (KOH). Subsequently, whole mount bone staining was performed with an Alizarin red S/KOH solution, followed by clearing in a glycerol series. Observations of the skeleton were made using a binocular microscope (Leica M165FC) with a fluorescent unit and equipped with a Leica DFC 450 C camera. Results: In total, 15 skeletal deformity types were identified and defined: (i) fusion, (ii) compression, (iii) vertical shift of the vertebra, (iv) fractures, (v) curvy ribs), (vi) extra intramembranous bone on the arches and spines (associated elements)and vertebral centra, (vii) bent associated elements, (viii) double associated elements, (ix) detached associated elements, (x) notochord tissue mineralization, (xi) intervertebral ligament mineralization, (xii) lordosis, (xii) kyphosis, (xiii) scoliosis and (xiv) torsion of the vertebral column around the central axis. Conclusion(s): Deep phenotyping of zebrafish models for skeletal disease will lead to better understanding of expressed phenotypes and of the underlying mechanisms and may lead to identifying new therapeutic targets.

The degeneration of intervertebral disc (IVD) tissue, initiated following the disappearance of notochordal cells (NCs), is characterized by the decreased number of nucleus pulposus (NP) cells (NPCs) and extracellular matrix. Transplanting proper cells into the IVD may sustain cell numbers, resulting in the synthesis of new matrix; this represents a minimally invasive regenerative therapy. However, the lack of cells with a correct phenotype severely hampers the development of regenerative therapy. The present study aimed to investigate whether porcine NC‑rich NP tissue stimulates bone marrow‑derived mesenchymal stem cell (BM‑MSC) differentiation toward NC‑like cells, which possess promising regenerative ability, for the treatment of disc degeneration diseases. BM‑MSCs were successfully isolated from porcine femurs and tibiae, which expressed CD90 and CD105 markers and did not express CD45. Differentiation induction experiments revealed that the isolated cells had osteogenic and adipogenic differentiation potential. When co‑cultured with NC‑rich NP tissue, the BM‑MSCs successfully differentiated into NC‑like cells. Cell morphological analysis revealed that the cells exhibited an altered morphology, from a shuttle‑like to a circular one, and the expression of NC marker genes, including brachyury, keratin‑8, and keratin‑18, was enhanced, and the cells exhibited the ability to generate aggrecan and collagen II. Taken together, the findings of the present study demonstrated that the primarily isolated and cultured BM‑MSCs may be stimulated to differentiate into NC‑like cells by porcine NC‑rich NP explants, potentially providing an ideal cell source for regenerative therapies for disc degeneration diseases.

Notochordal cells play a pivotal role in vertebral column patterning, contributing to the formation of the inner architecture of intervertebral discs (IVDs). Their disappearance during development has been associated with reduced repair capacity and IVD degeneration. Notochordal remnants are known to cause chordomas, a highly invasive bone cancer associated with late diagnosis. Understanding the impact of neoplastic cells during development and on the surrounding vertebral column could open avenues for earlier intervention and therapeutics. We investigated the impact of transformed notochord cells in the zebrafish skeleton using a RAS expressing line in the notochord under the control of the Kita promoter, with the advantage of adulthood endurance. Transformed cells caused damage in the notochord and destabilised the sheath layer triggering a wound repair mechanism, with enrolment of sheath cells (col9a2+) and expression of wt1b, similar to induced notochord wounds. Moreover, increased recruitment of neutrophils and macrophages, displaying abnormal behaviour in proximity to the notochord sheath and transformed cells, supported parallels between chordomas, wound and inflammation. Cancerous notochordal cells interfere with differentiation of sheath cells to form chordacentra domains leading to fusions and vertebral clefts during development. Adults displayed IVD irregularities reminiscent of degeneration; reduced bone mineral density, increased osteoclast activity; while disorganised osteoblasts and collagen indicate impaired bone homeostasis. By depleting inflammatory cells, we abrogated chordoma development and rescued the skeletal features of the vertebral column. Therefore, we showed that transformed notochord cells alter the skeleton during life, causing a wound-like phenotype and activating chronic wound response, suggesting parallels between chordoma, wound, IVD degeneration and inflammation, highlighting inflammation as a promising target for future therapeutics.

Ventral bending of the embryonic tail within the chorion is an evolutionarily conserved morphogenetic event in both invertebrates and vertebrates. However, the complexity of the anatomical structure of vertebrate embryos makes it difficult to experimentally identify the mechanisms underlying embryonic folding. This study investigated the mechanisms underlying embryonic tail bending in chordates. To further understand the mechanical role of each tissue, we also developed a physical model with experimentally measured parameters to simulate embryonic tail bending. Actomyosin asymmetrically accumulated at the ventral side of the notochord, and cell proliferation of the dorsal tail epidermis was faster than that in the ventral counterpart during embryonic tail bending. Genetic disruption of actomyosin activity and inhibition of cell proliferation dorsally caused abnormal tail bending, indicating that both asymmetrical actomyosin contractility in the notochord and the discrepancy of epidermis cell proliferation are required for tail bending. In addition, asymmetrical notochord contractility was sufficient to drive embryonic tail bending, whereas differential epidermis proliferation was a passive response to mechanical forces. These findings showed that asymmetrical notochord contractility coordinates with differential epidermis proliferation mechanisms to drive embryonic tail bending. This article has an associated ‘The people behind the papers’ interview.

Direct intercellular communication via gap junctions has an important role in the development of the nervous system, ranging from cell migration and neuronal differentiation to the formation of neuronal activity patterns. This study characterized and compared the specific spatio-temporal expression patterns of connexins (Cxs) 37, 43 and 45 during early human developmental stages (since the 5th until the 10th developmental week) in the spinal cord (SC) and dorsal root ganglia (DRG) using double immunofluorescence and transmission electron microscopy. We found the expression of all three investigated Cxs during early human development in all the areas of interest, in the SC, DRG, developing paravertebral ganglia of the sympathetic trunk, notochord and all three meningeal layers, with predominant expression of Cx37. Comparing the expression of different Cxs between distinct developmental periods, we did not find significant differences. Specific spatio-temporal pattern of Cxs expression might reflect their relevance in the development of all areas of interest via cellular interconnectivity and synchronization during the late embryonic and early fetal period of human development.

The tail resorption process was an inevitable and pivotal transformation during amphibian metamorphosis. The present study investigated the mechanisms of tail resorption through histological and transcriptome analysis in Rana chensinensis. The results showed that tail resorption was initiated before the onset of metamorphic climax, and dramatically regressed after metamorphic climax by external-morphology measurement. The drastic disintegration of tail muscle and notochord occurred at Gs42-44, which were consistent with the trend of thyroid follicular cell height. Besides, expression level analysis and functional annotation of DEGs (differentially expressed genes) were conducted through RNA-seq analysis of the tail. Our study also analyzed the expression of genes related to oxidative stress, autophagy, apoptosis and degradation of cellular components in the tail of R. chensinensis. This study enriched the R. chensinensis transcriptome database and laid the foundation of further analysis of tail resorption.

Matrix metalloproteinase-2 (a.k.a. Gelatinase A, or Mmp2 in zebrafish) is known to have roles in pathologies such as arthritis, in which its function is protective, as well as in cancer metastasis, in which it is activated as part of the migration and invasion of metastatic cells. It is also required during development and the regeneration of tissue architecture after wound healing, but its roles in tissue remodelling are not well understood. Gelatinase A is activated post-translationally by proteolytic cleavage, making information about its transcription and even patterns of protein accumulation difficult to relate to biologically relevant activity. Using a transgenic reporter of endogenous Mmp2 activation in zebrafish, we describe its accumulation and post-translational proteolytic activation during the embryonic development of the tail. Though Mmp2 is expressed relatively ubiquitously, it seems to be active only at specific locations and times. Mmp2 is activated robustly in the neural tube and in maturing myotome boundaries. It is also activated in the notochord during body axis straightening, in patches scattered throughout the epidermal epithelium, in the gut, and on cellular protrusions extending from mesenchymal cells in the fin folds. The activation of Mmp2 in the notochord, somite boundaries and fin folds associates with collagen remodelling in the notochord sheath, myotome boundary ECM and actinotrichia respectively. Mmp2 is likely an important effector of ECM remodelling during the morphogenesis of the notochord, a driving structure in vertebrate development. It also appears to function in remodelling the ECM associated with growing epithelia and the maturation of actinotrichia in the fin folds, mediated by mesenchymal cell podosomes.