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Bodo Christ - One of the best experts on this subject based on the ideXlab platform.
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Formation and differentiation of avian somite derivatives.
Advances in experimental medicine and biology, 2008Co-Authors: Bodo Christ, Martin ScaalAbstract:During somite maturation, the ventral half of the epithelial somite disintegrates into the mesenchymal Sclerotome, whereas the dorsal half forms a transitory epithelial sheet, the dermomyotome, lying in between the Sclerotome and the surface ectoderm. The dermomyotome is the source of the majority of the mesodermal tissues in the body, giving rise to cell types as different as muscle, connective tissue, endothelium and cartilage. Thus, the dermomyotome is the most important turntable of mesodermal cell fate choice in the vertebrate embryo. Sclerotome development is characterized by a cranio-caudal polarization, resegmentation and axial identity. Its formation is controlled by signals from the notochord, the neural tube, the lateral plate mesoderm and the myotome. These signals and cross-talk between somite cells lead to the separation of various subdomains, like the central, ventral, dorsal and lateral Sclerotome. Here, we discuss the current knowledge on the formation of the dermomyotome and the mechanisms leading to the development of the various dermomyotomal derivatives, with special emphasis on the development of musculature and dermis. We further discuss the molecular control of sclerotomal subdomain formation and cell type specification.
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Formation and differentiation of the avian dermomyotome
Anatomy and Embryology, 2004Co-Authors: Martin Scaal, Bodo ChristAbstract:During somite maturation, the ventral half of the epithelial somite disintegrates into the mesenchymal Sclerotome, whereas the dorsal half forms a transitory epithelial sheet, the dermomyotome, lying in between the Sclerotome and the surface ectoderm. The dermomyotome is the source of most of the mesodermal tissues in the body, giving rise to cell types as different as muscle, connective tissue, endothelium, and cartilage. Thus, the dermomyotome is the most important turntable of mesodermal cell fate choice in the vertebrate embryo. Here, we discuss the current knowledge on the formation of the dermomyotome and the mechanisms leading to the development of the various dermomyotomal derivatives, with special emphasis on the development of musculature and dermis.
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Formation and differentiation of the avian Sclerotome
Anatomy and Embryology, 2004Co-Authors: Bodo Christ, Ruijin Huang, Martin ScaalAbstract:The avian Sclerotome forms by epitheliomesenchymal transition of the ventral half-somite. Sclerotome development is characterized by a craniocaudal polarization, resegmentation, and axial identity. Its formation is controlled by signals from the notochord, the neural tube, the lateral plate mesoderm, and the myotome. These signals and crosstalk between somite cells lead to the separation of various subdomains, such as the central and ventral Sclerotomes that express Pax1 under the control of Sonic hedgehog and Noggin, and the dorsal and lateral Sclerotome that do not express Pax1 and are controlled by Bmp-4. Further subdomains that give rise to specific derivatives are the syndetome, neurotome, meningotome, and arthrotome. The molecular control of subdomain formation and cell type specification is discussed.
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the development of the avian vertebral column
Anatomy and Embryology, 2000Co-Authors: Bodo Christ, Ruijin Huang, Jörg WiltingAbstract:Segmentation of the paraxial mesoderm leads to somite formation. The underlying molecular mechanisms involve the oscillation of ”clock-genes” like c-hairy-1 and lunatic fringe indicative of an implication of the Notch signaling pathway. The cranio-caudal polarity of each segment is already established in the cranial part of the segmental plate and accompanied by the expression of genes like Delta1, Mesp1, Mesp2, Uncx-1, and EphA4 which are restricted to one half of the prospective somite. Dorsoventral compartmentalization of somites leads to the development of the dermomyotome and the Sclerotome, the latter forming as a consequence of an epithelio-to-mesenchymal transition of the ventral part of the somite. The Sclerotome cells express Pax-1 and Pax-9, which are induced by notochordal signals mediated by sonic hedgehog (Shh) and noggin. The craniocaudal somite compartmentalization that becomes visible in the Sclerotomes is the prerequisite for the segmental pattern of the peripheral nervous system and the formation of the vertebrae and ribs, whose boundaries are shifted half a segment compared to the Sclerotome boundaries. Sclerotome development is characterized by the formation of three subcompartments giving rise to different parts of the axial skeleton and ribs. The lateral Sclerotome gives rise to the laminae and pedicles of the neural arches and to the ribs. Its development depends on signals from the notochord and the myotome. The ventral Sclerotome giving rise to the vertebral bodies and intervertebral discs is made up of Pax-1 expressing cells that have invaded the perinotochordal space. The dorsal Sclerotome is formed by cells that migrate from the dorso-medial angle of the Sclerotome into the space between the roof plate of the neural tube and the dermis. These cells express the genes Msx1 and Msx2, which are induced by BMP-4 secreted from the roof plate, and they later form the dorsal part of the neural arch and the spinous process. The formation of the ventral and dorsal Sclerotome requires directed migration of Sclerotome cells. The regionalization of the paraxial mesoderm occurs by a combination of functionally Hox genes, the Hox code, and determines the segment identity. The development of the vertebral column is a consequence of a segment-specific balance between proliferation, apoptosis and differentiation of cells.
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Sclerotomal origin of the ribs.
Development (Cambridge England), 2000Co-Authors: Ruijin Huang, Jörg Wilting, Qixia Zhi, Corina Schmidt, Beate Brand-saberi, Bodo ChristAbstract:The somites of vertebrate embryos give rise to Sclerotomes and dermomyotomes. The Sclerotomes form the axial skeleton, whereas the dermomyotomes give rise to all trunk muscles and the dermis of the back. The ribs were thought to be ventral processes of the axial skeleton and therefore to be derived from the Sclerotomes; however, recently a dermomyotomal origin of the distal rib (the costal shaft) was suggested, with only the proximal parts (head and neck of the rib) being of sclerotomal origin. We have re-investigated the development of the ribs in quail-chick chimeras and carried out three experimental series. (1) Single dermomyotomes and (2) single Sclerotomes were grafted homotopically, and (3) the ectoderm overlying the unsegmented paraxial mesoderm was removed in the prospective thoracic region. We found that the cells of the dermomyotome gave rise to epaxial and hypaxial trunk muscles, dermis of the back and endothelial cells, but not to ribs. Cells of the Sclerotome formed the axial skeleton and all parts of the ribs. Ablation of the ectoderm, which affects dermomyotome development, results in severe malformations of the ribs, probably due to disturbed interactions between dermomyotome and Sclerotome. Our results strongly confirm the traditional view of the sclerotomal origin of the ribs.
Rosa Serra - One of the best experts on this subject based on the ideXlab platform.
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Antagonism of BMP signaling is insufficient to induce fibrous differentiation in primary Sclerotome.
Experimental cell research, 2019Co-Authors: Ga I. Ban, Sade Williams, Rosa SerraAbstract:Abstract Sclerotome is the embryonic progenitor of the axial skeleton. It was previously shown that Tgfbr2 is required in Sclerotome for differentiation of fibrous skeletal tissues including the annulus fibrosus of the intervertebral disc. Alternatively, BMP signaling is required to form the vertebral body through chondrogenesis. In addition, TGFβ added to Sclerotome cultures induces expression of markers for fibrous tissue differentiation but not cartilage or bone. The mechanism of how TGFβ signaling regulates this lineage decision in Sclerotome is not known and could be due to the production of instructive or inhibitory signals or a combination of the two. Here we show that TGFβ antagonizes BMP/ Smad1/5 signaling in primary Sclerotome likely through regulation of Noggin, an extracellular BMP antagonist, to prevent chondrogenesis. We then tested whether inhibition of BMP signaling, and inhibition of chondrogenesis, is sufficient to push cells toward the fibrous cell fate. While Noggin inhibited BMP/ Smad1/5 signaling and the formation of chondrogenic nodules in Sclerotome cultures; Noggin and inhibition of BMP signaling through Gremlin or DMH2 were insufficient to induce fibrous tissue differentiation. The results suggest inhibition of BMP signaling is not sufficient to stimulate fibrous tissue differentiation and additional signals are likely required. We propose that TGFβ has a dual role in regulating Sclerotome fate. First, it inhibits BMP signaling potentially through Noggin to prevent chondrogenesis and, second, it provides an unknown instructive signal to promote fibrous tissue differentiation in Sclerotome. The results have implications for the design of stem cell-based therapies for skeletal diseases.
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IVD Development: Nucleus Pulposus Development and Sclerotome Specification
Current molecular biology reports, 2018Co-Authors: Bashar Alkhatib, Sade Williams, Ga I. Ban, Rosa SerraAbstract:Purpose of Review Intervertebral discs (IVD) are derived from embryonic notochord and Sclerotome. The nucleus pulposus is derived from notochord while other connective tissues of the spine are derived from Sclerotome. This manuscript will review the past 5 years of research into IVD development.
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Development of the Intervertebral Disc
The Intervertebral Disc, 2013Co-Authors: Megan K. Cox, Rosa SerraAbstract:Intervertebral discs are derived from embryonic structures called the Sclerotome and notochord (Paavola et al. 1980; Theiler 1988; Rufai et al. 1995). The nucleus pulposus, the cushioning core of the mature intervertebral disc, is derived from the notochord, while the annulus fibrosus, which provides the structural properties of the disc, is derived from Sclerotome (Christ et al. 2004, 2007; Christ and Scaal 2008). The Sclerotome is derived from the somites, transient structures that determine the segmented nature of the embryo. In response to signals from the notochord and floor plate of the neural tube, the maturing somites undergo dorsal-ventral compartmentalization establishing the dermomyotome and Sclerotome, the latter forming most of the connective tissues of the future axial skeleton. The development of the Sclerotome is characterized by proliferation and expansion of cells as well as the formation of three subcompartments: ventral, lateral, and dorsal. The ventral Sclerotome gives rise to the vertebral bodies and annulus fibrosus and is made up of Pax-1-expressing cells that have invaded the perinotochordal space (Monsoro-Burq et al. 1994; Peters et al. 1999).
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pdgf mediates tgfβ induced migration during development of the spinous process
Developmental Biology, 2012Co-Authors: Ying Wang, Rosa SerraAbstract:Mechanisms mediating closure of the dorsal vertebrae are not clear. Previously, we showed that deletion of TGFβ type II receptor (Tgfbr2) in Sclerotome in mice results in failure in the formation of the spinous process, mimicking spina bifida occulta, a common malformation in humans. In this study, we aimed to determine whether missing dorsal structures in Tgfbr2 mutant mice were due to defects in mesenchymal migration and to clarify mechanism of TGFβ-mediated migration. First, we showed that gross alterations in dorsal vertebrae were apparent by E16.5days in Tgfbr2 mutants. In addition, histological staining showed that the mesenchyme adjacent to the developing cartilage was thin compared to controls likely due to reduced proliferation and migration of these cells. Next, we used a chemotaxis migration assay to show that TGFβ promotes migration in mixed cultures of embryonic Sclerotome and associated mesenchyme. TGFβ stimulated expression of PDGF ligands and receptors in the cultures and intact PDGF signaling was required for TGFβ-mediated migration. Since PDGF ligands are expressed in the Sclerotome-derived cartilage where Tgfbr2 is deleted and the receptors are predominantly expressed in the adjacent mesenchyme, we propose that TGFβ acts on the Sclerotome to regulate expression of PDGF ligands, which then act on the associated mesenchyme in a paracrine fashion to mediate proliferation, migration and subsequent differentiation of the adjacent Sclerotome.
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tgfbr2 regulates the maintenance of boundaries in the axial skeleton
Developmental Biology, 2006Co-Authors: Michael O Baffi, Molly Moran, Rosa SerraAbstract:Previously, we showed that deletion of the TGF-β type II receptor (Tgfbr2) in Type II Collagen (Col2a) expressing cells results in defects in the development of the axial skeleton. Defects included a reduction in size and alterations in the shape of specific vertebral elements. Anterior lateral and dorsal elements of the vertebrae were missing or irregularly shaped. Vertebral bodies were only mildly affected, but the intervertebral disc (IVD) was reduced or missing. In this manuscript, we show that alterations in the initiation or proliferation of cartilage are not detected in the axial skeleton. However, the expression domain of Fibromodulin (Fmod), a marker of the IVD, was reduced and the area of the future IVD contained peanut agglutinin (PNA) staining cartilage. Next, we show that the expression domains of Pax1 and Pax9, which are preferentially expressed in the caudal Sclerotome, are expanded over the entire rostral to caudal length of the Sclerotome segment. Dorsal–ventral patterning was not affected in these mice as accessed by expression of Pax1, Pax9, and Msx1. Proliferation was modestly reduced in the loose cells of the Sclerotome. The results suggest that signaling through Tgfbr2 regulates the maintenance of boundaries in the Sclerotome and developing axial skeleton.
Chaya Kalcheim - One of the best experts on this subject based on the ideXlab platform.
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Neural tube development depends on notochord-derived sonic hedgehog released into the Sclerotome.
Development (Cambridge England), 2020Co-Authors: Nitza Kahane, Chaya KalcheimAbstract:Sonic hedgehog (Shh), produced in the notochord and floor plate, is necessary for both neural and mesodermal development. To reach the myotome, Shh has to traverse the Sclerotome and a reduction of sclerotomal Shh affects myotome differentiation. By investigating loss and gain of Shh function, and floor-plate deletions, we report that sclerotomal Shh is also necessary for neural tube development. Reducing the amount of Shh in the Sclerotome using a membrane-tethered hedgehog-interacting protein or Patched1, but not dominant active Patched, decreased the number of Olig2+ motoneuron progenitors and Hb9+ motoneurons without a significant effect on cell survival or proliferation. These effects were a specific and direct consequence of Shh reduction in the mesoderm. In addition, grafting notochords in a basal but not apical location, vis-a-vis the tube, profoundly affected motoneuron development, suggesting that initial ligand presentation occurs at the basal side of epithelia corresponding to the Sclerotome-neural tube interface. Collectively, our results reveal that the Sclerotome is a potential site of a Shh gradient that coordinates the development of mesodermal and neural progenitors.
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Neural tube development depends on notochord-derived Sonic hedgehog released into the Sclerotome
2019Co-Authors: Nitza Kahane, Chaya KalcheimAbstract:Abstract Sonic hedgehog (Shh), produced in notochord and floor plate, is necessary both for neural and mesodermal development. To reach the myotome, Shh has to traverse the Sclerotome. By loss and gain of Shh function, and floor plate deletions, we report that sclerotomal Shh is also necessary for neural tube development. Reducing the amount of Shh in Sclerotome by membrane-tethered hedgehog-interacting protein or by Patched1, but not by dominant active Patched, decreased motoneuron numbers while also compromising myotome differentiation. These effects were a specific and direct consequence of reducing Shh. In addition, grafting notochords in a basal, but not apical location vis-a-vis the tube, profoundly affected motoneuron development, suggesting that initial ligand presentation occurs at the basal side of epithelia corresponding to the Sclerotome-neural tube interface. Collectively, our results reveal that the Sclerotome is a potential site of a Shh gradient that coordinates development of mesodermal and neural progenitors. Summary statement Shh that transits through the Sclerotome is presented to the neuroepithelium from its basal aspect to affect motoneuron development.
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F-Spondin, Expressed in Somite Regions Avoided by Neural Crest Cells, Mediates Inhibition of Distinct Somite Domains to Neural Crest Migration
Neuron, 1999Co-Authors: Anat Debby-brafman, Tal Burstyn-cohen, Avihu Klar, Chaya KalcheimAbstract:Abstract Neural crest (NC) cells migrate exclusively into the rostral half of each Sclerotome, where they avoid the dermomyotome and the paranotochordal Sclerotome. F-spondin is expressed in these inhibitory regions and throughout the caudal halves. In vitro bioassays of NC spreading on substrates of rostral or caudal epithelial–half somites (RS or CS, respectively) revealed that NC cells adopt on RS a fibroblastic morphology, whereas on CS they fail to flatten. F-spondin inhibited flattening of NC cells on RS. Conversely, F-spondin antibodies prevented rounding up of NC cells on CS. Addition of F-spondin to trunk explants inhibited NC migration into the Sclerotome, and treatment of embryos with anti-F-spondin antibodies yielded migration into otherwise inhibitory sites. Thus, somite-derived F-spondin is an inhibitory signal involved in patterning the segmental migration of NC cells and their topographical segregation within the RS.
Clifford J Tabin - One of the best experts on this subject based on the ideXlab platform.
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Genetic analysis of interactions between the somitic muscle, cartilage and tendon cell lineages during mouse development.
Development (Cambridge England), 2005Co-Authors: Ava E. Brent, Thomas Braun, Clifford J TabinAbstract:Proper formation of the musculoskeletal system requires the coordinated development of the muscle, cartilage and tendon lineages arising from the somitic mesoderm. During early somite development, muscle and cartilage emerge from two distinct compartments, the myotome and Sclerotome, in response to signals secreted from surrounding tissues. As the somite matures, the tendon lineage is established within the dorsolateral Sclerotome, adjacent to and beneath the myotome. We examine interactions between the three lineages by observing tendon development in mouse mutants with genetically disrupted muscle or cartilage development. Through analysis of embryos carrying null mutations in Myf5 and Myod1, hence lacking both muscle progenitors and differentiated muscle, we identify an essential role for the specified myotome in axial tendon development, and suggest that absence of tendon formation in Myf5/Myod1 mutants results from loss of the myotomal FGF proteins, which depend upon Myf5 and Myod1 for their expression, and are required, in turn, for induction of the tendon progenitor markers. Our analysis of Sox5/Sox6 double mutants, in which the chondroprogenitors are unable to differentiate into cartilage, reveals that the two cell fates arising from the Sclerotome, axial tendon and cartilage are alternative lineages, and that cartilage differentiation is required to actively repress tendon development in the dorsolateral Sclerotome.
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FGF acts directly on the somitic tendon progenitors through the Ets transcription factors Pea3 and Erm to regulate scleraxis expression
Development (Cambridge England), 2004Co-Authors: Ava E. Brent, Clifford J TabinAbstract:During somite development, a fibroblast growth factor (FGF) signal secreted from the myotome induces formation of a scleraxis (Scx)-expressing tendon progenitor population in the Sclerotome, at the juncture between the future lineages of muscle and cartilage. While overexpression studies show that the entire Sclerotome is competent to express Scx in response to FGF signaling, the normal Scx expression domain includes only the anterior and posterior dorsal Sclerotome. To understand the molecular basis for this restriction, we examined the expression of a set of genes involved in FGF signaling and found that several members of the Fgf8 synexpression group are co-expressed with Scx in the dorsal Sclerotome. Of particular interest were the Ets transcription factors Pea3 and Erm, which function as transcriptional effectors of FGF signaling. We show here that transcriptional activation by Pea3 and Erm in response to FGF signaling is both necessary and sufficient for Scx expression in the somite, and propose that the domain of the somitic tendon progenitors is regulated both by the restricted expression of Pea3 and Erm, and by the precise spatial relationship between these Ets transcription factors and the FGF signal originating in the myotome.
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Ectopic expression of Sonic hedgehog alters dorsal-ventral patterning of somites
Cell, 1994Co-Authors: Randy L. Johnson, Ed Laufer, Robert D. Riddle, Clifford J TabinAbstract:Abstract Differentiation of somites into Sclerotome, dermatome, and myotome is controlled by a complex set of inductive interactions. The ability of axial midline tissues, the notochord and floor plate, to induce Sclerotome has been well documented and has led to models in which ventral somite identity is specified by signals derived from the notochord and floor plate. Herein, we provide evidence that Sonic hedgehog , a vertebrate homolog of the Drosophila segment polarity gene hedgehog , is a signal produced by the notochord and floor plate that directs ventral somite differentiation. Sonic hedgehog is expressed in ventral midline tissues at critical times during somite specification and has the ability, when ectopically expressed, to enhance the formation of Sclerotome and antagonize the development of dermatome.
Rudi Balling - One of the best experts on this subject based on the ideXlab platform.
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pax1 and pax9 synergistically regulate vertebral column development
Development, 1999Co-Authors: Heiko Peters, Bettina Wilm, Norio Sakai, Kenji Imai, Richard L Maas, Rudi BallingAbstract:The paralogous genes Pax1 and Pax9 constitute one group within the vertebrate Pax gene family. They encode closely related transcription factors and are expressed in similar patterns during mouse embryogenesis, suggesting that Pax1 and Pax9 act in similar developmental pathways. We have recently shown that mice homozygous for a defined Pax1 null allele exhibit morphological abnormalities of the axial skeleton, which is not affected in homozygous Pax9 mutants. To investigate a potential interaction of the two genes, we analysed Pax1/Pax9 double mutant mice. These mutants completely lack the medial derivatives of the Sclerotomes, the vertebral bodies, intervertebral discs and the proximal parts of the ribs. This phenotype is much more severe than that of Pax1 single homozygous mutants. In contrast, the neural arches, which are derived from the lateral regions of the Sclerotomes, are formed. The analysis of Pax9 expression in compound mutants indicates that both spatial expansion and upregulation of Pax9 expression account for its compensatory function during Sclerotome development in the absence of Pax1. In Pax1/Pax9 double homozygous mutants, formation and anteroposterior polarity of Sclerotomes, as well as induction of a chondrocyte-specific cell lineage, appear normal. However, instead of a segmental arrangement of vertebrae and intervertebral disc anlagen, a loose mesenchyme surrounding the notochord is formed. The gradual loss of Sox9 and Collagen II expression in this mesenchyme indicates that the Sclerotomes are prevented from undergoing chondrogenesis. The first detectable defect is a low rate of cell proliferation in the ventromedial regions of the Sclerotomes after Sclerotome formation but before mesenchymal condensation normally occurs. At later stages, an increased number of cells undergoing apoptosis further reduces the area normally forming vertebrae and intervertebral discs. Our results reveal functional redundancy between Pax1 and Pax9 during vertebral column development and identify an early role of Pax1 and Pax9 in the control of cell proliferation during early Sclerotome development. In addition, our data indicate that the development of medial and lateral elements of vertebrae is regulated by distinct genetic pathways.
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Expression of avian Pax1 and Pax9 is intrinsically regulated in the pharyngeal endoderm, but depends on environmental influences in the paraxial mesoderm
Developmental Biology, 1996Co-Authors: Thomas Müller, Annette Neubuser, Bodo Christ, Haruhiko Koseki, Rudi Balling, Cecilia Ebensperger, Jörg WiltingAbstract:Pax1 and Pax9 represent a subfamily of paired-box-containing genes. In vertebrates, Pax1 and Pax9 transcripts have been found specifically in mesodermal tissues and the pharyngeal endoderm. Pax1 expression in the Sclerotomes has been shown to be indispensable for proper formation of the axial skeleton, but expression of Pax1 in the endoderm has not been studied in detail. We have cloned the chick homologue of the murine Pax9 gene. Our results show that transcripts of Pax1 and Pax9 are first detectable in the prospective foregut endoderm of headfold-stage avian embryos. Endodermal expression correlates with the highly proliferative zones of the folding foregut and evaginating pharyngeal pouches. In later stages, Pax1 and Pax9 are expressed in overlapping but distinct patterns within the developing Sclerotomes and limb buds. From grafting experiments we conclude that activation of pharyngeal Pax1 and Pax9 expression is an intrinsic property of the endoderm, not requiring midline structures or head mesoderm. In contrast, notochord is required to induce Pax1 in competent Sclerotomes. Here we show that in vitro there is a cranio-caudal gradient of inductive capacity in the notochord. This coincides with the graded expression of Pax1 and Pax9 along the cranio-caudal axis in 2- to 3-day-old embryos. Furthermore, paraxial head mesoderm shows no competence to express Pax1. Finally, in vitro we find counteracting influences on notochord signaling by lateral tissues (lateral plate, intermediate mesoderm), leading to an inhibition of Sonic hedgehog (Shh) expression in notochord and floor plate, as well as Pax1 and Pax9 expression in Sclerotomes. Taken together, our results demonstrate that different mechanisms regulate expression of Pax1 and Pax9 in foregut and Sclerotome, but suggest a common function for both genes in the two tissues that is promoting proliferation and preventing fusion of neighboring blastemas.
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Pax genes and Sclerotome development
Seminars in Cell & Developmental Biology, 1996Co-Authors: Rudi Balling, Annette Neubuser, Bodo ChristAbstract:Abstract Differentiation of somites leads to the development of dermomyotome and Sclerotome with the latter forming after an epithelial-mesenchymal transition of the ventral part of the somite. Inductive effects of the notochord are required for differentiation of the Sclerotome and for proper formation of the axial skeleton, the inductive effect of the notochord being mediated by sonic hedgehog (SHH), the mammalian homologue of the Drosophila segment polarity gene hedgehog . Shh acts by antagonizing the activity of the cAMP dependent protein kinase A (Pka). Pax1 and Pax9 are paired box containing genes expressed in the developing Sclerotome that may be involved in mediating the inductive effects of the notochord. Loss of Pax1 function in mice leads to severe abnormalities in Sclerotome differentiation and vertebral column formation.
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the role of pax 1 in axial skeleton development
Development, 1994Co-Authors: J Wallin, Bodo Christ, Haruhiko Koseki, Jörg Wilting, Rudiger Fritsch, Rudi BallingAbstract:Previous studies have identified a single amino-acid substitution in the transcriptional regulator Pax-1 as the cause of the mouse skeletal mutant undulated (un). To evaluate the role of Pax-1 in the formation of the axial skeleton we have studied Pax-1 protein expression in early Sclerotome cells and during subsequent embryonic development, and we have characterized the phenotype of three different Pax-1 mouse mutants, un, undulated-extensive (unex) and Undulated short-tail (Uns). In the Uns mutation the whole Pax-1 locus is deleted, resulting in the complete absence of Pax-1 protein in these mice. The other two genotypes are interpreted as hypomorphs. We conclude that Pax-1 is necessary for normal vertebral column formation along the entire axis, although the severity of the phenotype is strongest in the lumbar region and the tail. Pax-1-deficient mice lack vertebral bodies and intervertebral discs. The proximal part of the ribs and the rib homologues are also missing or severely malformed, whereas neural arches are nearly normal. Pax-1 is thus required for the development of the ventral parts of vertebrae. Embryonic analyses reveal that although Sclerotomes are formed in mutant embryos, abnormalities can be detected from day 10.5 p.c. onwards. The phenotypic analyses also suggest that the notochord still influences vertebral body formation some days after the Sclerotomes are formed. Furthermore, the notochord diameter is larger in mutant embryos from day 12 p.c., due to increased cell proliferation. In the strongly affected genotypes the notochord persists as a rod-like structure and the nucleus pulposus is never properly formed. Since the notochord is Pax-1-negative these findings suggest a bidirectional interaction between notochord and paraxial mesoderm. The availability of these Pax-1 mutant alleles permitted us to define an early role for Pax-1 in Sclerotome patterning as well as a late role in intervertebral disc development. Our observations suggest that Pax-1 function is required for essential steps in ventral Sclerotome differentiation, i.e. for the transition from the mesenchymal stage to the onset of chondrogenesis.
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The ventralizing effect of the notochord on somite differentiation in chick embryos
Anatomy and Embryology, 1993Co-Authors: Beate Brand-saberi, Cecilia Ebensperger, Rudi Balling, Jörg Wilting, Bodo ChristAbstract:The dorso-ventral pattern formation of the somites becomes manifest by the formation of the epithelially organized dorsal dermomyotome and the mesenchymal ventrally situated Sclerotome. While the dermomyotome gives rise to dermis and muscle, the Sclerotome differentiates into cartilage and bone of the axial skeleton. The onset of muscle differentiation can be visualized by immunohistochemistry for proteins associated with muscle contractility, e.g. desmin. The Sclerotome cells and the epithelial ventral half of the somite express Pax-1 , a member of a gene family with a sequence similarity to Drosophila paired-box-containing genes. In the present study, changes of Pax-1 expression were studied after grafting an additional notochord into the paraxial mesoderm region. The influence of the notochord and the floor-plate on dermomyotome formation and myotome differentiation has also been investigated. The notochord is found to exert a ventralizing effect on the establishment of the dorso-ventral pattern in the somites. Notochord grafts lead to a suppression of the formation and differentiation of the dorsal somitic derivatives. Simultaneously, a widening of the Pax-1 -expressing domain in the Sclerotome can be observed. In contrast, grafted roof-plate and aorta do not interfere with dorso-ventral patterning of the somitic derivatives.