Dynamic Assignment and Maintenance of Positional Identity in the Ventral Neural Tube by the Morphogen Sonic Hedgehog

Dessaud, Éric; Ribes, Vanessa; Balaskas, Nikolaos; Yang, Lin; Pierani, Alessandra; Kicheva, Anna; Novitch, Bennett G.; Briscoe, James; Sasai, Noriaki

doi:10.1371/journal.pbio.1000382

Cited by 190 publications

(263 citation statements)

References 84 publications

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“…These data also suggest that this remaining expression of pMN, p2 and p1 genes is sufficient to specify the postmitotic cells that we observe in the zebrafish ventral spinal cord in the absence of Hh signalling. Our results are consistent with data from Dessaud and colleagues (Dessaud et al, 2010) that suggest that in amniotes the duration of Shh signalling is as important as the levels of signalling for specifying distinct ventral spinal cord fates, although our data suggest that it is continued inhibition of Gli repressor activity (see below) that is important, rather than Hh signalling per se. Taken together, the simplest model for reconciling these different mouse and zebrafish phenotypes is that, in zebrafish, Gli repressor activity is not present in the ventral spinal cord until the early to mid-somitogenesis stages and that this is too late to repress the initial expression of p2 and p1 domain transcription factors and the formation of V2 and V1 cells, although it is sufficient to repress p2 and p1 domain expression at later stages.…”

Section: Research Articlesupporting

confidence: 92%

Roles of Hedgehog pathway components and retinoic acid signalling in specifying zebrafish ventral spinal cord neurons

et al. 2011

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SUMMARYIn mouse, Hedgehog (Hh) signalling is required for most ventral spinal neurons to form. Here, we analyse the spinal cord phenotype of zebrafish maternal-zygotic smoothened (MZsmo) mutants that completely lack Hh signalling. We find that most V3 domain cells and motoneurons are lost, whereas medial floorplate still develops normally and V2, V1 and V0v cells form in normal numbers. This phenotype resembles that of mice that lack both Hh signalling and Gli repressor activity. Ventral spinal cord progenitor domain transcription factors are not expressed at 24 hpf in zebrafish MZsmo mutants. However, pMN, p2 and p1 domain markers are expressed at early somitogenesis stages in these mutants. This suggests that Gli repressor activity does not extend into zebrafish ventral spinal cord at these stages, even in the absence of Hh signalling. Consistent with this, ectopic expression of Gli3R represses ventral progenitor domain expression at these early stages and knocking down Gli repressor activity rescues later expression. We investigated whether retinoic acid (RA) signalling specifies ventral spinal neurons in the absence of Hh signalling. The results suggest that RA is required for the correct number of many different spinal neurons to form. This is probably mediated, in part, by an effect on cell proliferation. However, V0v, V1 and V2 cells are still present, even in the absence of both Hh and RA signalling. We demonstrate that Gli1 has a Hh-independent role in specifying most of the remaining motoneurons and V3 domain cells in embryos that lack Hh signalling, but removal of Gli1 activity does not affect more dorsal neurons.

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Section: Research Articlesupporting

confidence: 92%

Roles of Hedgehog pathway components and retinoic acid signalling in specifying zebrafish ventral spinal cord neurons

et al. 2011

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“…Experimental work in Drosophila and in vertebrates indicates that the Hh signaling pathway is subject to extensive feedback among elements of the pathway, most notably that of the Hh receptor patched (ptc) (Chen and Struhl, 1996;Marigo and Tabin, 1996). Furthermore, the combination of experimental and modeling studies on developing fly wings and on vertebrate neural tube and limbs have uncovered new roles for this feedback in the dynamics of Hh gradient formation, in its robustness and in the generation of distinct patterns of target gene expression (Briscoe et al, 2001;Saha and Schaffer, 2006;Dessaud et al, 2007;Dessaud et al, 2008;González et al, 2008;Nahmad and Stathopoulos, 2009;Dessaud et al, 2010;Irons et al, 2010;Probst et al, 2011;Balaskas et al, 2012). Therefore, the iteration between mathematical modeling and experimentation is emerging as a productive way of illuminating the problem of Hh morphogen action during organ growth and patterning.…”

Section: Introductionmentioning

confidence: 99%

A Hh-driven gene network controls specification, pattern and size of the Drosophila simple eyes

Aguilar-Hidalgo

Dominguez-Cejudo

Amore³

et al. 2013

Development

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SUMMARYDuring development, extracellular signaling molecules interact with intracellular gene networks to control the specification, pattern and size of organs. One such signaling molecule is Hedgehog (Hh). Hh is known to act as a morphogen, instructing different fates depending on the distance to its source. However, how Hh, when signaling across a cell field, impacts organ-specific transcriptional networks is still poorly understood. Here, we investigate this issue during the development of the Drosophila ocellar complex. The development of this sensory structure, which is composed of three simple eyes (or ocelli) located at the vertices of a triangular patch of cuticle on the dorsal head, depends on Hh signaling and on the definition of three domains: two areas of eya and so expression -the prospective anterior and posterior ocelli -and the intervening interocellar domain. Our results highlight the role of the homeodomain transcription factor engrailed (en) both as a target and as a transcriptional repressor of hh signaling in the prospective interocellar region. Furthermore, we identify a requirement for the Notch pathway in the establishment of en maintenance in a Hh-independent manner. Therefore, hh signals transiently during the specification of the interocellar domain, with en being required here for hh signaling attenuation. Computational analysis further suggests that this network design confers robustness to signaling noise and constrains phenotypic variation. In summary, using genetics and modeling we have expanded the ocellar gene network to explain how the interaction between the Hh gradient and this gene network results in the generation of stable mutually exclusive gene expression domains. In addition, we discuss some general implications our model may have in some Hh-driven gene networks.

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“…Recent fate-mapping studies based on the Cre-loxP strategy indicated that the Nkx2-2 and Olig2 cell lineages may share a common origin (Wu et al, 2006;Dessaud et al, 2007Dessaud et al, , 2010Holz et al, 2010;Chen et al, 2011;Wang et al, 2011), a result that is supported by the analysis of the temporal expression profile of several transcription factors (Jeong and McMahon, 2005;Lek et al, 2010). It is therefore important to understand how the Olig2/Nkx2-2 double-positive (Olig2 + /Nkx2-2 + ) cells diversify into Olig2 + pMN progenitors and Nkx2-2 + p3 progenitors.…”

Section: Introductionmentioning

confidence: 99%

Sp8 plays a supplementary role to Pax6 in establishing the pMN/p3 domain boundary in the spinal cord

Liu

Qiu

et al. 2014

Development

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Progenitor cells are segregated into multiple domains along the dorsoventral axis of the vertebrate neural tube, and each progenitor domain generates particular types of neurons. Selective crossrepressive interactions between pairs of class I and class II transcription factors play important roles in patterning neural progenitors into domains with clear boundaries. Here, we provide evidence that the zinc-finger protein Sp8 plays a supplementary role to Pax6 in establishing the pMN/p3 domain boundary through mutually repressive interactions with the class II protein Nkx2-2. The ventral limit of Sp8 expression is complementary to the dorsal limit of Nkx2-2 expression at the pMN/p3 boundary. Sp8 and Nkx2-2 exert cross-repressive interactions, and changing the expression of Sp8 and Nkx2-2 is coupled with pMN and p3 progenitor fate conversion. Sp8 exerts its neural patterning activities by acting as a transcriptional activator. The expression of a repressive form of Sp8 results in the selective inhibition of motor neuron generation and the ectopic induction of Nkx2-2 expression. Sp8 expression is positively regulated by, but not completely dependent on, Pax6. Furthermore, whereas loss of Pax6 function alone results in disruption of the pMN/p3 domain boundary only in the rostral levels of the spinal cord, loss of both Sp8 and Pax6 functions results in disruption of the pMN/p3 domain boundary along the whole rostrocaudal axis of the spinal cord. We conclude that Sp8 plays a supplementary role to Pax6 in specifying the pMN over p3 progenitor fate through cross-repressive interactions with Nkx2-2.

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Dynamic Assignment and Maintenance of Positional Identity in the Ventral Neural Tube by the Morphogen Sonic Hedgehog

Abstract: During development of the vertebrate neural tube, cells acquire their positional identity from not only the spatial level of the Sonic Hedgehog signaling gradient, but also the temporal duration.

Cited by 190 publications

References 84 publications

Roles of Hedgehog pathway components and retinoic acid signalling in specifying zebrafish ventral spinal cord neurons

Roles of Hedgehog pathway components and retinoic acid signalling in specifying zebrafish ventral spinal cord neurons

A Hh-driven gene network controls specification, pattern and size of the Drosophila simple eyes

Sp8 plays a supplementary role to Pax6 in establishing the pMN/p3 domain boundary in the spinal cord

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