Deciphering the specificity and function of FGD RhoGEFs during skin development

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Morphogenesis refers to all the cellular rearrangements occurring in a developing tissue that allow an organism to acquire its proper and characteristic shape. To this date, the molecular mechanisms that govern this crucial step of embryonic development are still poorly understood. Molecules from the Rho GTPases family are rising as key regulators of morphogenesis due to their ability to govern cellular architecture. In mammals, there is 20 Rho GTPases and more than 150 regulators that are part of the RhoGEFs, RhoGAPs and RhoGDIs families. Still, only a few molecules from these intricate signaling networks have been studied in depth. This is preventing us from appreciating the full scope of Rho GTPases roles. Given the large complexity involved and the importance of studying the role of these molecules in an animal model to fully grasp the extent of their biological functions, it is essential to develop methods that are less labour intensive than classic genetic mouse models. The mouse skin is an ideal system to study morphogenesis processes since it develops through a succession of sophisticated cellular rearrangements, but the molecular details of these processes remain poorly comprehended. I recently took advantage of a new technology that allows the genetic transformation of skin progenitors via the injection of lentiviral particles in the amniotic cavity of living mouse embryo. Using this technique, I developed a high-throughput screening methodology that permitted the identification of several new regulators of skin morphogenesis among the Rho GTPases signaling networks. Intriguingly, 3 members of the poorly characterized FGD family of RhoGEFs, namely FGD1, FGD2 and FGD5, were among the candidates uncovered. These molecules have been shown to activate Rho GTPases in cells but their biological functions are unknown. I hypothesize that FGD1, FGD2 and FGD5 each regulates different aspects of skin development through their interaction with specific effector proteins. Using state-of-the art multidisciplinary approaches such as lentiviral injection, cell imaging and proteomic, this NSERC research program will focus on understanding the role of FGD RhoGEFs during skin morphogenesis. This work will provide fundamental insights into the molecular mechanisms that regulate skin development and it will be the first analysis of the function of these molecules in this tissue. Additionally, this work will contribute to our knowledge of how individual Rho GTPases coordinate cellular behaviors during embryonic development.