Epithelial-mesenchymal feedback signalling during vertebrate organogenesis : genetic analysis of BMP-Gremlin1 antagonistic interactions

Branching morphogenesis of the metanephric kidney relies on an intricate molecular system that controls a highly regulated
developmental program. Metanephric kidney organogenesis involves a complex system of epithelial mesenchymal interactions
that orchestrate an elaborate epithelial branching process. Although it has already been shown that BMP signalling is involved
in this process the present study reveals the functional importance and relevant interactions of BMPs with the antagonist
GREMLIN1 (GREM1). Our genetic and molecular analysis identifies GREM1 as an essential negative modulator of BMP4 signaling
during initiation of kidney branching morphogenesis. GREM1 is essential for positioning the ureteric bud, initiating its outgrowth
and proper epithelial branching. GREM1 is not only required to antagonize BMP4 but genetic analysis of its interactions with BMP7
reveals a more general role in modulating BMP signaling. In light of these GREM1 interactions with BMP4 and BMP7, my Ph.D. research
indicates that GREM1 orchestrates initiation and progression of epithelial branching by establishing spatiotemporal control of BMP
activity in the mesenchyme surrounding the Wolffian duct, ureteric bud and likely also branching epithelium.