Role of F-BAR proteins in neuronal development

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DESCRIPTION (provided by applicant): Both membrane protrusion and invagination are fundamental cellular processes and are therefore tightly regulated. Importantly, these apparently antagonistic processes control the size and molecular composition of the plasma membrane, are essential for cellular migration and require actin polymerization. However, there is little dat on how membrane protrusion and invagination are integrated in cellular function, especially in the nervous system. F-BAR proteins are a superfamily of proteins involved in membrane curvature sensing and deformation through their F-BAR domain, positioning them as potentially important players in both of these processes. Structurally, they form a curved dimer that self-multimerizes around endocytic vesicles, causing their elongation into tubules. The CIP4 family of proteins (TOCA1, FBP17 and CIP4) is one family of F-BAR proteins that also bind actin-associated proteins. Like other F-BAR proteins, the CIP4 family is thought to function primarily in membrane invagination and endocytosis, but our recent work has implicated CIP4 in neuronal membrane protrusion as well. We have recently discovered that CIP4 transfection induces actin-based ribs and veils around the periphery of cortical neurons. These ribs and veils are similar to filopodia and lamellipodia, respectively, and result in an scalloped lamellipodia, fille with thin actin bundles connected by actin-rich veils of membrane. In primary cortical neurons CIP4 family proteins are specifically associated with the protruding edges of ribs and veils, positioning them at the nexus of membrane deformation and actin polymerization. In this proposal we will test the following novel hypotheses: 1) F-BAR proteins of the CIP4 family act in a context- specific manner in neurons and non-neuronal cells by interacting with a distinct subset of proteins and 2) CIP4 functions in neurons by inhibiting axon/dendrite outgrowth during migration. This work will provide fundamental insights into how proteins may serve context-specific functions in different cell types and how neurons coordinate membrane protrusion and invagination during migration and axon formation. CIP4 has been implicated in Huntington's disease and several forms of cancer, underscoring the importance of understanding how this family of proteins may function in a context-specific fashion in different cell types.