Genetic analysis of Gremlin functions during mouse organogenesis

Abstract

Epithelial-mesenchymal signaling interactions are critical events that regulate organogenesis. The research presented in this thesis establishes that the extra-cellular BMP antagonist Gremlin is essential to initiate, maintain and propagate such epithelial-mesenchymal feedback signaling during limb and metanephric kidney organogenesis. Furthermore, modulating BMP activity by Gremlin-mediated antagonism appears to be critical to epithelial morphogenesis. In particular, Gremlin-mediated BMP antagonism is essential for proper differentiation of AER epithelial cells, a key event in initiation of distal limb bud outgrowth. Moreover, Gremlin is also involved in the differentiation of lung epithelial cells that play a major role in supporting gas exchange. Finally, genetic studies establish that the Gremlin loss-of-function allele generated by gene targeting is allelic to the mouse limb deformity (ld) mutation. These studies show that Gremlin, not Formin, is the gene whose disruption causes the ld limb phenotype. The ld limb phenotype is caused either by disruption of the Gremlin transcription unit or by disruption of distant cis-regulatory elements with features of a global control region (GCR) that regulates activation of both Gremlin and Formin expression in the posterior limb bud mesenchyme.