The molecular robustness of the self-regulatory limb bud signaling system
The genomic landscape encoding Gremlin1, a BMP antagonist, provides an excellent model to study individual and coordinate functions of cis–regulatory modules (CRMs) regulating the spatio-temporal expression dynamics during progression of limb bud development. The Grem1 cis-regulatory landscape is embedded in a 500kb TAD that encodes multiple evolutionary conserved CRMs. The ongoing analysis of the Grem1 cis-regulatory landscape is providing experimental evidence for genetic robustness. The functional analysis of the CRMs regulating Grem1 expression dynamics is revealing significant redundancy and/or complementation among the enhancers making up the cis-regulatory landscape. Using mouse Grem1 alleles carrying deletions of different CRMs, we are obtaining increasing evidence for a second level of robustness at the signaling system level. In order to understand this, the aim of my project is to profile the gene expression patterns in different Grem1 mutant alleles with the aim to elucidate how the signaling systems adapts to changes in Grem1 expression to maintain this genetic robustness.