A Homeodomain Protein Code Specifies Progenitor Cell Identity and Neuronal Fate in the Ventral Neural Tube

The secretion of Sonic hedgehog (Shh) from the notochord and floor plate appears to generate a ventral-to-dorsal gradient of Shh activity that directs progenitor cell identity and neuronal fate in the ventral neural tube. In principle, the establishment of this Shh activity gradient could be achieved through the graded distribution of the Shh protein itself, or could depend on additional cell surface or secreted proteins that modify the response of neural cells to Shh. Cells of the neural plate differentiate from a region of the ectoderm that has recently expressed high levels of BMPs, raising the possibility that prospective ventral neural cells are exposed to residual levels of BMP activity. We have examined whether modulation of the level of BMP signaling regulates neural cell responses to Shh, and thus might contribute to the patterning of cell types in the ventral neural tube. Using an in vitro assay of neural cell differentiation we show that BMP signaling markedly alters neural cell responses to Shh signals, eliciting a ventral-to-dorsal switch in progenitor cell identity and neuronal fate. BMP signaling is regulated by secreted inhibitory factors, including noggin and follistatin, both of which are expressed in or adjacent to the neural plate. Conversely, follistatin but not noggin produces a dorsal-to-ventral switch in progenitor cell identity and neuronal fate in response to Shh both in vitro and in vivo. These results suggest that the specification of ventral neural cell types depends on the integration of Shh and BMP signaling activities. The net level of BMP signaling within neural tissue may be regulated by follistatin and perhaps other BMP inhibitors secreted by mesodermal cell types that flank the ventral neural tube.

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Groucho-Mediated Transcriptional Repression Establishes Progenitor Cell Pattern and Neuronal Fate in the Ventral Neural Tube

Cell ◽

10.1016/s0092-8674(01)00283-5 ◽

2001 ◽

Vol 104 (6) ◽

pp. 861-873 ◽

Cited By ~ 246

Author(s):

Jonas Muhr ◽

Elisabet Andersson ◽

Madelen Persson ◽

Thomas M. Jessell ◽

Johan Ericson

Keyword(s):

Neural Tube ◽

Transcriptional Repression ◽

Progenitor Cell ◽

Cell Pattern ◽

Neuronal Fate ◽

Ventral Neural Tube

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Pax6 Controls Progenitor Cell Identity and Neuronal Fate in Response to Graded Shh Signaling

Cell ◽

10.1016/s0092-8674(00)80323-2 ◽

1997 ◽

Vol 90 (1) ◽

pp. 169-180 ◽

Cited By ~ 595

Author(s):

J Ericson ◽

P Rashbass ◽

A Schedl ◽

S Brenner-Morton ◽

A Kawakami ◽

...

Keyword(s):

Progenitor Cell ◽

Shh Signaling ◽

Cell Identity ◽

Neuronal Fate

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Myogenesis in paraxial mesoderm: preferential induction by dorsal neural tube and by cells expressing Wnt-1

Development ◽

10.1242/dev.121.11.3675 ◽

1995 ◽

Vol 121 (11) ◽

pp. 3675-3686 ◽

Cited By ~ 40

Author(s):

H.M. Stern ◽

A.M. Brown ◽

S.D. Hauschka

Keyword(s):

Neural Tube ◽

Muscle Development ◽

Paraxial Mesoderm ◽

Myogenic Response ◽

Dorsal Neural Tube ◽

Ventral Neural Tube ◽

Myogenic Induction ◽

Inductive Activity

Previous studies have demonstrated that the neural tube/notochord complex is required for skeletal muscle development within somites. In order to explore the localization of myogenic inducing signals within the neural tube, dorsal or ventral neural tube halves were cultured in contact with single somites or pieces of segmental plate mesoderm. Somites and segmental plates cultured with the dorsal half of the neural tube exhibited 70% and 85% myogenic response rates, as determined by immunostaining for myosin heavy chain. This response was slightly lower than the 100% response to whole neural tube/notochord, but was much greater than the 30% and 10% myogenic response to ventral neural tube with and without notochord. These results demonstrate that the dorsal neural tube emits a potent myogenic inducing signal which accounts for most of the inductive activity of whole neural tube/notochord. However, a role for ventral neural tube/notochord in somite myogenic induction was clearly evident from the larger number of myogenic cells induced when both dorsal neural tube and ventral neural tube/notochord were present. To address the role of a specific dorsal neural tube factor in somite myogenic induction, we tested the ability of Wnt-1-expressing fibroblasts to promote paraxial mesoderm myogenesis in vitro. We found that cells expressing Wnt-1 induced a small number of somite and segmental plate cells to undergo myogenesis. This finding is consistent with the localized dorsal neural tube inductive activity described above, but since the ventral neural tube/notochord also possesses myogenic inductive capacity yet does not express Wnt-1, additional inductive factors are likely involved.

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Cell-autonomous shift from axial to paraxial mesodermal development in zebrafish floating head mutants

Development ◽

10.1242/dev.121.12.4257 ◽

1995 ◽

Vol 121 (12) ◽

pp. 4257-4264 ◽

Cited By ~ 25

Author(s):

M.E. Halpern ◽

C. Thisse ◽

R.K. Ho ◽

B. Thisse ◽

B. Riggleman ◽

...

Keyword(s):

Neural Tube ◽

Single Cells ◽

Floor Plate ◽

Paraxial Mesoderm ◽

Wild Type ◽

Genetic Mosaics ◽

Essential Step ◽

Ventral Neural Tube ◽

Mesodermal Development

Zebrafish floating head mutant embryos lack notochord and develop somitic muscle in its place. This may result from incorrect specification of the notochord domain at gastrulation, or from respecification of notochord progenitors to form muscle. In genetic mosaics, floating head acts cell autonomously. Transplanted wild-type cells differentiate into notochord in mutant hosts; however, cells from floating head mutant donors produce muscle rather than notochord in wild-type hosts. Consistent with respecification, markers of axial mesoderm are initially expressed in floating head mutant gastrulas, but expression does not persist. Axial cells also inappropriately express markers of paraxial mesoderm. Thus, single cells in the mutant midline transiently co-express genes that are normally specific to either axial or paraxial mesoderm. Since floating head mutants produce some floor plate in the ventral neural tube, midline mesoderm may also retain early signaling capabilities. Our results suggest that wild-type floating head provides an essential step in maintaining, rather than initiating, development of notochord-forming axial mesoderm.

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The zebrafish T-box genesno tailandspadetailare required for development of trunk and tail mesoderm and medial floor plate

Development ◽

10.1242/dev.129.14.3311 ◽

2002 ◽

Vol 129 (14) ◽

pp. 3311-3323 ◽

Cited By ~ 6

Author(s):

Sharon L. Amacher ◽

Bruce W. Draper ◽

Brian R. Summers ◽

Charles B. Kimmel

Keyword(s):

Embryonic Development ◽

Neural Tube ◽

Transcriptional Regulators ◽

Floor Plate ◽

Wild Type ◽

T Box ◽

No Tail ◽

Ventral Neural Tube ◽

Plate Formation ◽

In Cells

T-box genes encode transcriptional regulators that control many aspects of embryonic development. Here, we demonstrate that the mesodermally expressed zebrafish spadetail (spt)/VegT and no tail (ntl)/Brachyury T-box genes are semi-redundantly and cell-autonomously required for formation of all trunk and tail mesoderm. Despite the lack of posterior mesoderm in spt–;ntl– embryos, dorsal-ventral neural tube patterning is relatively normal, with the notable exception that posterior medial floor plate is completely absent. This contrasts sharply with observations in single mutants, as mutations singly in ntl or spt enhance posterior medial floor plate development. We find that ntl function is required to repress medial floor plate and promote notochord fate in cells of the wild-type notochord domain and that spt and ntl together are required non cell-autonomously for medial floor plate formation, suggesting that an inducing signal present in wild-type mesoderm is lacking in spt–;ntl– embryos.

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The control of rostrocaudal pattern in the developing spinal cord: specification of motor neuron subtype identity is initiated by signals from paraxial mesoderm

Development ◽

10.1242/dev.125.6.969 ◽

1998 ◽

Vol 125 (6) ◽

pp. 969-982 ◽

Cited By ~ 10

Author(s):

M. Ensini ◽

T.N. Tsuchida ◽

H.G. Belting ◽

T.M. Jessell

Keyword(s):

Spinal Cord ◽

Motor Neuron ◽

Motor Neurons ◽

Neural Tube ◽

Motor Behavior ◽

Neural Tube Closure ◽

Paraxial Mesoderm ◽

Homeodomain Protein ◽

Mesodermal Cell ◽

Developing Spinal Cord

The generation of distinct classes of motor neurons is an early step in the control of vertebrate motor behavior. To study the interactions that control the generation of motor neuron subclasses in the developing avian spinal cord we performed in vivo grafting studies in which either the neural tube or flanking mesoderm were displaced between thoracic and brachial levels. The positional identity of neural tube cells and motor neuron subtype identity was assessed by Hox and LIM homeodomain protein expression. Our results show that the rostrocaudal identity of neural cells is plastic at the time of neural tube closure and is sensitive to positionally restricted signals from the paraxial mesoderm. Such paraxial mesodermal signals appear to control the rostrocaudal identity of neural tube cells and the columnar subtype identity of motor neurons. These results suggest that the generation of motor neuron subtypes in the developing spinal cord involves the integration of distinct rostrocaudal and dorsoventral patterning signals that derive, respectively, from paraxial and axial mesodermal cell groups.

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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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BMP signaling patterns the dorsal and intermediate neural tube via regulation of homeobox and helix-loop-helix transcription factors

Development ◽

10.1242/dev.129.10.2459 ◽

2002 ◽

Vol 129 (10) ◽

pp. 2459-2472 ◽

Cited By ~ 15

Author(s):

John R. Timmer ◽

Charlotte Wang ◽

Lee Niswander

Keyword(s):

Transcription Factors ◽

Neural Tube ◽

Transforming Growth Factor ◽

Cell Types ◽

Neural Cell ◽

Bmp Signaling ◽

Expression Domain ◽

Cell Identity ◽

Dorsoventral Axis ◽

Helix Loop Helix

In the spinal neural tube, populations of neuronal precursors that express a unique combination of transcription factors give rise to specific classes of neurons at precise locations along the dorsoventral axis. Understanding the patterning mechanisms that generate restricted gene expression along the dorsoventral axis is therefore crucial to understanding the creation of diverse neural cell types. Bone morphogenetic proteins (BMPs) and other transforming growth factor β (TGFβ) proteins are expressed by the dorsal-most cells of the neural tube (the roofplate) and surrounding tissues, and evidence indicates that they play a role in assigning cell identity. We have manipulated the level of BMP signaling in the chicken neural tube to show that BMPs provide patterning information to both dorsal and intermediate cells. BMP regulation of the expression boundaries of the homeobox proteins Pax6, Dbx2 and Msx1 generates precursor populations with distinct developmental potentials. Within the resulting populations, thresholds of BMP act to set expression domain boundaries of developmental regulators of the homeobox and basic helix-loop-helix (bHLH) families, ultimately leading to the generation of a diversity of differentiated neural cell types. This evidence strongly suggests that BMPs are the key regulators of dorsal cell identity in the spinal neural tube.

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Neurogenin 1 (Neurog1) expression in the ventral neural tube is mediated by a distinct enhancer and preferentially marks ventral interneuron lineages

Developmental Biology ◽

10.1016/j.ydbio.2010.02.012 ◽

2010 ◽

Vol 340 (2) ◽

pp. 283-292 ◽

Cited By ~ 25

Author(s):

Herson I. Quiñones ◽

Trisha K. Savage ◽

James Battiste ◽

Jane E. Johnson

Keyword(s):

Neural Tube ◽

Ventral Neural Tube

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