Sonic hedgehog is required for survival of both myogenic and chondrogenic somitic lineages

In vertebrates, the medial moieties of the somites give rise to the vertebrae and epaxial muscles, which develop in close relationship with the axial organs, neural tube and notochord. The lateral moieties contribute to the ribs and to limb and body wall muscles (hypaxial muscles) after a phase of lateral and ventral migration. Surgical ablation of the neural tube and notochord in the chick embryo during segmentation and early differentiation of the somites (day 2 of incubation) does not affect primary development of the hypaxial muscles, but leads to a complete absence of epaxial muscles, vertebrae and ribs, due to cell death in the somites. Here we demonstrate that cell death, which occurs within 24 hours of excision of the axial organs, affects both myogenic and chondrogenic cell lineages defined, respectively, by the expression of MyoD and Pax-1 genes. In contrast, Pax-3 transcripts, normally present in cells giving rise to hypaxial muscles, are preserved in the excised embryos. Backgrafting either the ventral neural tube or the notochord allows survival of MyoD- and Pax-1-expressing cells. Similarly, Sonic hedgehog-producing cells grafted in place of axial organs also rescue MyoD- and Pax-1-expressing cells from death and allow epaxial muscles, ribs and vertebrae to undergo organogenesis. These results demonstrate that the ventral neural tube and the notochord promote the survival of both myogenic and chondrogenic cell lineages in the somites and that this action is mediated by Sonic hedgehog.

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Direct action of the nodal-related signal cyclops in induction of sonic hedgehog in the ventral midline of the CNS

Development ◽

10.1242/dev.127.18.3889 ◽

2000 ◽

Vol 127 (18) ◽

pp. 3889-3897 ◽

Cited By ~ 4

Author(s):

F. Muller ◽

S. Albert ◽

P. Blader ◽

N. Fischer ◽

M. Hallonet ◽

...

Keyword(s):

Sonic Hedgehog ◽

Neural Tube ◽

Direct Action ◽

Brain Regions ◽

Floor Plate ◽

Ventral Midline ◽

Signal Transducers ◽

Step Model ◽

Ventral Neural Tube ◽

Differential Responsiveness

The secreted molecule Sonic hedgehog (Shh) is crucial for floor plate and ventral brain development in amniote embryos. In zebrafish, mutations in cyclops (cyc), a gene that encodes a distinct signal related to the TGF(beta) family member Nodal, result in neural tube defects similar to those of shh null mice. cyc mutant embryos display cyclopia and lack floor plate and ventral brain regions, suggesting a role for Cyc in specification of these structures. cyc mutants express shh in the notochord but lack expression of shh in the ventral brain. Here we show that Cyc signalling can act directly on shh expression in neural tissue. Modulation of the Cyc signalling pathway by constitutive activation or inhibition of Smad2 leads to altered shh expression in zebrafish embryos. Ectopic activation of the shh promoter occurs in response to expression of Cyc signal transducers in the chick neural tube. Furthermore an enhancer of the shh gene, which controls ventral neural tube expression, is responsive to Cyc signal transducers. Our data imply that the Nodal related signal Cyc induces shh expression in the ventral neural tube. Based on the differential responsiveness of shh and other neural tube specific genes to Hedgehog and Cyc signalling, a two-step model for the establishment of the ventral midline of the CNS is proposed.

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Differential regulation of the chick dorsal thoracic dermal progenitors from the medial dermomyotome

Development ◽

10.1242/dev.129.20.4763 ◽

2002 ◽

Vol 129 (20) ◽

pp. 4763-4772 ◽

Cited By ~ 2

Author(s):

Isabel Olivera-Martinez ◽

Sylvain Missier ◽

Sandrine Fraboulet ◽

Jacques Thélu ◽

Danielle Dhouailly

Keyword(s):

Neural Tube ◽

Central Region ◽

Differential Regulation ◽

Dorsal Neural Tube ◽

The Right ◽

Dermal Cells ◽

Epaxial Muscles ◽

Two Populations ◽

Axial Organs

The chick dorsal feather-forming dermis originates from the dorsomedial somite and its formation depends primarily on Wnt1 from the dorsal neural tube. We investigate further the origin and specification of dermal progenitors from the medial dermomyotome. This comprises two distinct domains: the dorsomedial lip and a more central region (or intervening zone) that derives from it. We confirm that Wnt1 induces Wnt11 expression in the dorsomedial lip as previously shown, and show using DiI injections that some of these cells, which continue to express Wnt11 migrate under the ectoderm, towards the midline, to form most of the dorsal dermis. Transplantation of left somites to the right side to reverse the mediolateral axis confirms this finding and moreover suggests the presence of an attractive or permissive environment produced by the midline tissues or/and a repellent or inadequate environment by the lateral tissues. By contrast, the dorsolateral dermal cells just delaminate from the surface of the intervening space, which expresses En1. Excision of the axial organs or the ectoderm, and grafting of Wnt1-secreting cells, shows that, although the two populations of dermal progenitors both requires Wnt1 for their survival, the signalling required for their specification differs. Indeed Wnt11 expression relies on dorsal neural tube-derived Wnt1, while En1 expression depends on the presence of the ectoderm. The dorsal feather-forming dermal progenitors thus appear to be differentially regulated by dorsal signals from the neural tube and the ectoderm, and derive directly and indirectly from the dorsomedial lip. As these two dermomyotomal populations are well known to also give rise to epaxial muscles, an isolated domain of the dermomyotome that contains only dermal precursors does not exist and none of the dermomyotomal domains can be considered uniquely as a dermatome.

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Zebrafishsmoothenedfunctions in ventral neural tube specification and axon tract formation

Development ◽

10.1242/dev.128.18.3497 ◽

2001 ◽

Vol 128 (18) ◽

pp. 3497-3509 ◽

Cited By ~ 16

Author(s):

Zoltán M. Varga ◽

Angel Amores ◽

Katharine E. Lewis ◽

Yi-Lin Yan ◽

John H. Postlethwait ◽

...

Keyword(s):

Sonic Hedgehog ◽

Neural Tube ◽

Hedgehog Signaling ◽

Floor Plate ◽

Slow Muscle ◽

Pituitary Cells ◽

Shh Signaling ◽

Ventral Neural Tube ◽

Hypothalamic Cells

Sonic hedgehog (Shh) signaling patterns many vertebrate tissues. shh mutations dramatically affect mouse ventral forebrain and floor plate but produce minor defects in zebrafish. Zebrafish have two mammalian Shh orthologs, sonic hedgehog and tiggy-winkle hedgehog, and another gene, echidna hedgehog, that could have overlapping functions. To examine the role of Hedgehog signaling in zebrafish, we have characterized slow muscle omitted (smu) mutants. We show that smu encodes a zebrafish ortholog of Smoothened that transduces Hedgehog signals. Zebrafish smoothened is expressed maternally and zygotically and supports specification of motoneurons, pituitary cells and ventral forebrain. We propose that smoothened is required for induction of lateral floor plate and a subpopulation of hypothalamic cells and for maintenance of medial floor plate and hypothalamic cells.

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13-P065 How long does ventral neural tube patterning need Sonic Hedgehog signaling?

Mechanisms of Development ◽

10.1016/j.mod.2009.06.538 ◽

2009 ◽

Vol 126 ◽

pp. S214

Author(s):

Noriaki Sasai ◽

Eric Dessaud ◽

Vanessa Ribes ◽

James Briscoe

Keyword(s):

Sonic Hedgehog ◽

Neural Tube ◽

Hedgehog Signaling ◽

Sonic Hedgehog Signaling ◽

Ventral Neural Tube

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Sonic hedgehog controls epaxial muscle determination through Myf5 activation

Development ◽

10.1242/dev.126.18.4053 ◽

1999 ◽

Vol 126 (18) ◽

pp. 4053-4063 ◽

Cited By ~ 19

Author(s):

A.G. Borycki ◽

B. Brunk ◽

S. Tajbakhsh ◽

M. Buckingham ◽

C. Chiang ◽

...

Keyword(s):

Sonic Hedgehog ◽

Neural Tube ◽

Mouse Embryo ◽

Body Wall ◽

Presomitic Mesoderm ◽

Dorsal Neural Tube ◽

Body Wall Muscles ◽

Myogenic Progenitor Cells ◽

Epaxial Muscle

Sonic hedgehog (Shh), produced by the notochord and floor plate, is proposed to function as an inductive and trophic signal that controls somite and neural tube patterning and differentiation. To investigate Shh functions during somite myogenesis in the mouse embryo, we have analyzed the expression of the myogenic determination genes, Myf5 and MyoD, and other regulatory genes in somites of Shh null embryos and in explants of presomitic mesoderm from wild-type and Myf5 null embryos. Our findings establish that Shh has an essential inductive function in the early activation of the myogenic determination genes, Myf5 and MyoD, in the epaxial somite cells that give rise to the progenitors of the deep back muscles. Shh is not required for the activation of Myf5 and MyoD at any of the other sites of myogenesis in the mouse embryo, including the hypaxial dermomyotomal cells that give rise to the abdominal and body wall muscles, or the myogenic progenitor cells that form the limb and head muscles. Shh also functions in somites to establish and maintain the medio-lateral boundaries of epaxial and hypaxial gene expression. Myf5, and not MyoD, is the target of Shh signaling in the epaxial dermomyotome, as MyoD activation by recombinant Shh protein in presomitic mesoderm explants is defective in Myf5 null embryos. In further support of the inductive function of Shh in epaxial myogenesis, we show that Shh is not essential for the survival or the proliferation of epaxial myogenic progenitors. However, Shh is required specifically for the survival of sclerotomal cells in the ventral somite as well as for the survival of ventral and dorsal neural tube cells. We conclude, therefore, that Shh has multiple functions in the somite, including inductive functions in the activation of Myf5, leading to the determination of epaxial dermomyotomal cells to myogenesis, as well as trophic functions in the maintenance of cell survival in the sclerotome and adjacent neural tube.

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Gli1 is a target of Sonic hedgehog that induces ventral neural tube development

Development ◽

10.1242/dev.124.13.2537 ◽

1997 ◽

Vol 124 (13) ◽

pp. 2537-2552 ◽

Cited By ~ 38

Author(s):

J. Lee ◽

K.A. Platt ◽

P. Censullo ◽

A. Ruiz i Altaba

Keyword(s):

Sonic Hedgehog ◽

Neural Tube ◽

Transcriptional Regulator ◽

Floor Plate ◽

Neural Plate ◽

Mouse Embryos ◽

Human Glioma ◽

Cubitus Interruptus ◽

Ventral Neural Tube ◽

Neural Tube Development

The vertebrate zinc finger genes of the Gli family are homologs of the Drosophila gene cubitus interruptus. In frog embryos, Gli1 is expressed transiently in the prospective floor plate during gastrulation and in cells lateral to the midline during late gastrula and neurula stages. In contrast, Gli2 and Gli3 are absent from the neural plate midline with Gli2 expressed widely and Gli3 in a graded fashion with highest levels in lateral regions. In mouse embryos, the three Gli genes show a similar pattern of expression in the neural tube but are coexpressed throughout the early neural plate. Because Gli1 is the only Gli gene expressed in prospective floor plate cells of frog embryos, we have investigated a possible involvement of this gene in ventral neural tube development. Here we show that Shh signaling activates Gli1 transcription and that widespread expression of endogenous frog or human glioma Gli1, but not Gli3, in developing frog embryos results in the ectopic differentiation of floor plate cells and ventral neurons within the neural tube. Floor-plate-inducing ability is retained when cytoplasmic Gli1 proteins are forced into the nucleus or are fused to the VP16 transactivating domain. Thus, our results identify Gli1 as a midline target of Shh and suggest that it mediates the induction of floor plate cells and ventral neurons by Shh acting as a transcriptional regulator.

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Anti-apoptotic role of Sonic hedgehog protein at the early stages of nervous system organogenesis

Development ◽

10.1242/dev.128.20.4011 ◽

2001 ◽

Vol 128 (20) ◽

pp. 4011-4020 ◽

Cited By ~ 3

Author(s):

Jean-Baptiste Charrier ◽

Françoise Lapointe ◽

Nicole M. Le Douarin ◽

Marie-Aimée Teillet

Keyword(s):

Cell Death ◽

Nervous System ◽

Chick Embryo ◽

Sonic Hedgehog ◽

Neural Tube ◽

Primitive Streak ◽

Embryo Cell ◽

Floor Plate ◽

Cell Death Program ◽

Midline Cells

In vertebrates the neural tube, like most of the embryonic organs, shows discreet areas of programmed cell death at several stages during development. In the chick embryo, cell death is dramatically increased in the developing nervous system and other tissues when the midline cells, notochord and floor plate, are prevented from forming by excision of the axial-paraxial hinge (APH), i.e. caudal Hensen’s node and rostral primitive streak, at the 6-somite stage (Charrier, J. B., Teillet, M.-A., Lapointe, F. and Le Douarin, N. M. (1999). Development126, 4771-4783). In this paper we demonstrate that one day after APH excision, when dramatic apoptosis is already present in the neural tube, the latter can be rescued from death by grafting a notochord or a floor plate fragment in its vicinity. The neural tube can also be recovered by transplanting it into a stage-matched chick embryo having one of these structures. In addition, cells engineered to produce Sonic hedgehog protein (SHH) can mimic the effect of the notochord and floor plate cells in in situ grafts and transplantation experiments. SHH can thus counteract a built-in cell death program and thereby contribute to organ morphogenesis, in particular in the central nervous system.

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Coordinate actions of BMPs, Wnts, Shh and noggin mediate patterning of the dorsal somite

Development ◽

10.1242/dev.124.20.3955 ◽

1997 ◽

Vol 124 (20) ◽

pp. 3955-3963 ◽

Cited By ~ 30

Author(s):

C. Marcelle ◽

M.R. Stark ◽

M. Bronner-Fraser

Keyword(s):

Molecular Marker ◽

Sonic Hedgehog ◽

Neural Tube ◽

Direct Action ◽

Floor Plate ◽

Dorsoventral Axis ◽

Dorsal Neural Tube ◽

Ventral Neural Tube ◽

Vertebrate Embryos ◽

Epaxial Muscle

Shortly after their formation, somites of vertebrate embryos differentiate along the dorsoventral axis into sclerotome, myotome and dermomyotome. The dermomyotome is then patterned along its mediolateral axis into medial, central and lateral compartments, which contain progenitors of epaxial muscle, dermis and hypaxial muscle, respectively. Here, we used Wnt-11 as a molecular marker for the medial compartment of dermomyotome (the ‘medial lip’) to demonstrate that BMP in the dorsal neural tube indirectly induces formation of the medial lip by up-regulating Wnt-1 and Wnt-3a (but not Wnt-4) expression in the neural tube. Noggin in the dorsal somite may inhibit the direct action of BMP on this tissue. Wnt-11 induction is antagonized by Sonic Hedgehog, secreted by the notochord and the floor plate. Together, our results show that the coordinated actions of the dorsal neural tube (via BMP and Wnts), the ventral neural tube/notochord (via Shh) and the somite itself (via noggin) mediates patterning of the dorsal compartment of the somite.

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