The role of LEM domain proteins in nuclear function

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DESCRIPTION (provided by applicant): Abstract: The nuclear lamina is a protein meshwork underneath the nuclear envelope (NE) that contributes to chromosome organization and gene regulation. One class of lamina proteins shares an ~40 amino acid LEM domain (LEM-D) that binds Barrier-to-Autointegration Factor (BAF), the conserved chromatin bridging protein. Mutations in genes encoding LEM-D proteins cause several human diseases known as laminopathies, including Emery-Dreifuss muscular dystrophy, cardio- myopathies and bone density disorders. These pathologies are tissue-restricted, even though the relevant LEM-D proteins are broadly expressed. Emerging data suggest that laminopathies arise from defects in homeostasis of mesenchymal stem cell populations. Our studies will define the function of LEM-D proteins in Drosophila to elucidate the role of the nuclear lamina in conferring tissue-specific regulation during development. These studies capitalize on our genetic isolation of mutations in three genes encoding LEM-D proteins. Our investigations have shown that the Drosophila LEM-D proteins have unique and overlapping developmental requirements, with evidence of age-enhanced phenotypes and a role in the morphogenesis of a mesenchymal stem cell niche. In this proposal, three aims are proposed. First, we will define requirements for dBAF during development, to understand how this chromatin binding protein contributes to the interphase functions of LEM-D proteins. Second, we will determine how the LEM-D is used to establish tissue- specific functions of this class of lamina proteins. Third, we will establish how LEM-D proteins contribute to critical regulatory pathways involved in the morphogenesis of the germline stem cell niche. Together, these investigations elucidate how BAF and LEM-D proteins work together in the NE to establish distinct nuclear lamina functions required for tissue development. As such, these studies will provide insights into molecular mechanisms of human laminopathies. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE The integrity and organization of the nucleus depends upon the function of the nuclear lamina, a protein meshwork that underlies the nuclear envelope. Alterations in nuclear lamina components cause several human diseases that are associated with tissue-restricted pathology, such as Emery-Dreifuss muscular dystrophy, myocardial diseases and bone density disorders, even though nuclear lamina proteins are found in all cells. Using genetic and molecular approaches in Drosophila, we will determine the function of one class of nuclear lamina proteins, the LEM domain proteins to provide insights into mechanisms of human disease of the nuclear lamina.