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Analysis of a global control region required for Gremlin activation: linking pre-patterning to SHH-dependent limb bud patterning


The vertebrate limb is a model of paradigmatic value to decipher the mechanisms controlling cell-cell signalling during organogenesis. It has been shown that Sonic Hedgehog (SHH orchestrates not only limb development, but is a key regulator of vertebrate organogenesis. In spite of the established central role of SHH, recent studies by R. Zeller and apos;s group show that the early limb bud is pre-patterned much before the onset of SHH signalling. Accordingly, posterior restricted activation of Gremlin occurs prior to establishment of SHH signalling and the host group established that a novel type of distant cis-regulatory region with the characteristics of a Global Control Region (GCR) modulates transcriptional activation of Gremlin in the limb bud mesenchyme. The major goal of my research is to identify and study the trans-acting signals and cis-acting elements in the GCR mediating activation of gene expression prior to SHH signalling.

This study will provide insights of general relevance as it aims to unravel the earliest molecular events that initiate polarization of nascent cells. To this aim, I will culture and manipulate mouse limb buds from different null mutant embryos. Furthermore, I will use the most advanced mouse reverse genetics technology to generate the transgenic mice for my studies. Finally, my analysis will be of potential biomedical relevance as evidence is mounting that disruption of long-range cis-regulation underlies a larger that expected number of congenital malformations and diseases. Indeed, this project contrasts with my previous research dealing primarily with phenotypic analysis of mouse embryos with impaired retinoic acid signalling. Therefore, this post-doctoral training period will allow me to substantially extend my technical and scientific knowledge.

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