Regulatory Interactions between Fibroblast Growth Factor, a Matrix Metalloproteinase and a Proteoglycan in the Control of Branching Morphogenesis

Thesis (Ph.D.)--University of Rochester. School of Medicine and Dentistry. Dept. of Biomedical Genetics, 2010.Fibroblast Growth Factor (FGF) is a central regulator of branching morphogenesis processes, such as angiogenesis or the development of branched organs including lung, kidney and salivary gland. The formation of the air sac during the development of the Drosophila tracheal system is a powerful and genetically accessible model to investigate how FGF signaling patterns such emerging structures. In this study, I characterized the Drosophila matrix metalloproteinase 2 (Mmp2) as an extracellular inhibitor of FGF function during tracheal development. RNAi mediated knock-down of Mmp2 disrupts the FGF-dependent patterning and morphogenesis of the air sac. Mmp2 expression in the developing air sac is induced by the Drosophila FGF homolog Branchless, and then feeds back on FGF signaling in a lateral inhibition mechanism that refines the precise air sac patterning. The inhibitory effect of Mmp2 on FGF signaling might be mediated by the proteolysis of Dally, a Drosophila Heparan Sulphate Proteoglycan (HSPG) and a known co-receptor of FGF receptor (FGFR). This thesis describes the identification of Dally as the first known substrate of Mmp2 and presents evidence in support of a mechanism by which the proteolysis of Dally mediates a spatial refinement of FGF-dependent patterning