Date of Award
embryogenesis, TGF-beta, GDF-3, embryonic development
The central aim of modern embryology is the resolution of the signaling pathways and transcriptional networks that direct embryonic development. After a century of rich experimental embryology, more recent molecular analyses of embryogenesis have revealed that communication between cells drives some of the most important events of development, including cell fate determination, growth, and morphogenesis. Among signaling factors, the TGF-Î² superfamily regulates all of these phenomena, and is the focus of this work. Despite significant progress in understanding the role of individual TGF-Î² ligands, their ultimate integration as a pathway is not fully understood and several ligands remain unexplored. In this work, I present the first comprehensive, comparative analysis of a mammalian-specific, structurally atypical TGF-Î² ligand, GDF-3. This work was first motivated by the finding that GDF-3 is strongly associated with the pluripotent state, and is one of the earliest ligands expressed in the mammalian embryo. However, nothing was previously known about its function in stem cells, or in normal embryonic development. Using frog embryos, mouse embryos, and mouse and human embryonic stem cells, I found that GDF-3 is a BMP-inhibitory ligand, adding to its unusual properties and extending the variety of regulatory strategies governing the TGF-Î² pathway. This inhibitory function endows GDF-3 with multiple activities, including the ability to directly induce neural tissue in frog embryos, thus highlighting the evolutionary conservation of mechanisms for neural formation. In mammalian embryonic stem cells, we found that GDF-3 opposes BMPs to regulate the balance of stemness and differentiation. These findings reveal the importance of negative, inhibitory information in the determination of the earliest embryonic cell fates. Further, I found that GDF-3 is required for normal patterning of the mouse embryo; its reduction causes a dramatic and unprecedented phenotype. In genetrap GDF-3 mutants, disorganized, distal migration of the notochord results in dorso-ventral re-arrangment of the entire embryo. This finding provides a genetic basis for dissecting the tightly coupled processes of morphogenesis and cell fate determination in the mammalian embryo.
Levine, Ariel, "The Role of GDF-3 in Patterning the Early Embryo" (2008). Student Theses and Dissertations. 13.