How do we get a perfect complement of digits?

Bastida, Ma Félix; Ros, María A.

doi:10.1016/j.gde.2008.06.009

Cited by 26 publications

(22 citation statements)

References 47 publications

(71 reference statements)

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“…A well-studied example in vertebrate development is the secreted protein Sonic hedgehog (Shh), which is responsible for conveying such information to cells of the ventral neural tube (Jessell, 2000) and to other tissues such as the limb bud (Bastida and Ros, 2008). In the neural tube, this activity is manifested in the patterned generation of distinct neuronal subtypes at stereotypic positions in response to graded Shh signaling by ventral midline cells.…”

Section: Introductionmentioning

confidence: 99%

A homeodomain feedback circuit underlies step-function interpretation of a Shh morphogen gradient during ventral neural patterning

et al. 2010

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SUMMARYThe deployment of morphogen gradients is a core strategy to establish cell diversity in developing tissues, but little is known about how small differences in the concentration of extracellular signals are translated into robust patterning output in responding cells. We have examined the activity of homeodomain proteins, which are presumed to operate downstream of graded Shh signaling in neural patterning, and describe a feedback circuit between the Shh pathway and homeodomain transcription factors that establishes non-graded regulation of Shh signaling activity. Nkx2 proteins intrinsically strengthen Shh responses in a feed-forward amplification and are required for ventral floor plate and p3 progenitor fates. Conversely, Pax6 has an opposing function to antagonize Shh signaling, which provides intrinsic resistance to Shh responses and is important to constrain the inductive capacity of the Shh gradient over time. Our data further suggest that patterning of floor plate cells and p3 progenitors is gated by a temporal switch in neuronal potential, rather than by different Shh concentrations. These data establish that dynamic, non-graded changes in responding cells are essential for Shh morphogen interpretation, and provide a rationale to explain mechanistically the phenomenon of cellular memory of morphogen exposure.

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Section: Introductionmentioning

confidence: 99%

A homeodomain feedback circuit underlies step-function interpretation of a Shh morphogen gradient during ventral neural patterning

et al. 2010

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“…A multitude of observations and experiments in the past years indicates that the signaling molecule sonic hedgehog (SHH) has a crucial role in specifying the number and identity of the digits by controlling both proliferation and patterning in the developing limb (Bastida and Ros, 2008;McMahon et al, 2003;Towers and Tickle, 2009).…”

Section: Introductionmentioning

confidence: 99%

A BMP-Shhnegative-feedback loop restrictsShhexpression during limb development

2009

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Normal patterning of tissues and organs requires the tight restriction of signaling molecules to well-defined organizing centers. In the limb bud, one of the main signaling centers is the zone of polarizing activity (ZPA) that controls growth and patterning through the production of sonic hedgehog (SHH). The appropriate temporal and spatial expression of Shh is crucial for normal limb bud patterning, because modifications, even if subtle, have important phenotypic consequences. However, although there is a lot of information about the factors that activate and maintain Shh expression, much less is known about the mechanisms that restrict its expression to the ZPA. In this study, we show that BMP activity negatively regulates Shh transcription and that a BMP-Shh negativefeedback loop serves to confine Shh expression. BMP-dependent downregulation of Shh is achieved by interfering with the FGF and Wnt signaling activities that maintain Shh expression. We also show that FGF induction of Shh requires protein synthesis and is mediated by the ERK1/2 MAPK transduction pathway. BMP gene expression in the posterior limb bud mesoderm is positively regulated by FGF signaling and finely regulated by an auto-regulatory loop. Our study emphasizes the intricacy of the crosstalk between the major signaling pathways in the posterior limb bud.

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“…However, these experiments have largely been overlooked but see (Towers et al, 2008) for a recent study that draws a similar conclusion. For other recent work on the role of growth in anteroposterior patterning see also (Zhu et al, 2008) and commentaries on these papers (Tabin and McMahon, 2008;Bastida and Ros, 2008;Francis-West and Hill, 2008).…”

Section: Integration Of Patterning and Growthmentioning

confidence: 99%

Generation of pattern and form in the developing limb

Towers¹,

Tickle²

2009

Int. J. Dev. Biol.

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The developing limb is a major model for pattern formation in vertebrate embryos. Many of the seminal discoveries of the mechanisms involved in patterning have been made using chick embryos because of the ease of manipulating their developing limbs. More recently, the molecular basis of limb pattern formation has been increasingly uncovered and now, with the availability of genomic resources, the genetic approaches available are even more powerful. Nevertheless, since the limb is ultimately built of cells, gene action must ultimately be translated into cell behaviour and a major challenge will be to integrate genetics with molecular and cellular biology. In this review, we will first outline the stages in limb development, the major interacting signalling pathways that pattern the limb and the molecules involved. We will describe fate maps of the developing limb, and discuss what is known about cellular activities including proliferation, death, adhesiveness, communication and migration during the patterning process. Finally we will explore how these cell activities produce form.

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How do we get a perfect complement of digits?

Cited by 26 publications

References 47 publications

A homeodomain feedback circuit underlies step-function interpretation of a Shh morphogen gradient during ventral neural patterning

A homeodomain feedback circuit underlies step-function interpretation of a Shh morphogen gradient during ventral neural patterning

A BMP-Shhnegative-feedback loop restrictsShhexpression during limb development

Generation of pattern and form in the developing limb

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