| TGF-beta growth factor superfamily members regulate major patterning and morphogenetic events during vertebrate embryogenesis. Activin, a member of the TGF-beta superfamily, has been extensively studied over the last 20 years for its activities to induce gastrulation movements and mesodermal patterning. My dissertation project is focused on the mechanism by which activin and nodal signaling controls the morphogenetic movements of the cells during Xenopus gastrulation.; The first part of my dissertation project is the characterization of a helix-loop-helix transcription factor XWBSCR11, which specifically binds to the activin response element of an organizer marker gene goosecoid (gsc). XWBSCR11 interacts with FoxH1 and Smad2, to form an active transcriptional complex that induces gsc expression in a ligand dependent manner. The second part describes a microarray approach to uncover new activin target genes. Among 13 authentic activin/nodal target genes identified from the microarray screening, a gene encoding the transmembrane protein FLRT3 is studied extensively in the following part. FLRT3 interacts with a small Rho family GTPase, Rnd1, and they function cooperatively to reduce cadherin-mediated cell adhesion. The loss-of-function studies show that FLRT3 and Rnd1 are required for the activin-induced convergence and extension movements. Interestingly, FLRT3 and Rnd1 do not change the overall expression level of cadherin, but affect the subcellular localization of cadherins, presumably by promoting their internalization. Altering the cellular adhesion characteristics by modulating cadherin subcellular localization is an attractive model to explain how TGF-beta affects the cellular morphology of the mesodermal tissue undergoing convergence and extension movements. In order to further investigate the molecular mechanism directly linking the FLRT3/Rnd1 pathway to a cadherin, I have searched for the molecules functioning downstream of Rnd1. The latest study implies that Rnd1 can form a complex with 14-3-3 zeta and Hakai (E3 ubiquitin ligase associated with cadherin). Spatiotemporal expression pattern analyses show that all of FLRT3/Rnd1, 14-3-3 zeta and Hakai are expressed in dorsal mesoderm in mid-gastrulae, indicating the possible mechanism underlying modulation of cadherin-mediated cell adhesion regulated by FLRT3/Rnd1. |
