The long-term goal of the proposed research is to understand the mechanisms that mediate neuronal migration in mammals. In the vertebrate embryo, neurons frequently migrate long distances to reach their final positions, where they assemble into complex networks that control physiology and behavior. Many human neurological disorders result when neurons either migrate aberrantly or fail to migrate. Therefore, it is essential to understand the mechanisms mediating migration of specific neuronal types, so that the causes of and potential remedies for human brain disorders can eventually be identified. Our studies may also impact efforts to induce stem cell-derived neurons to migrate accurately into brain regions damaged by injury or disease. The proposed work employs the migration of facial branchiomotor neurons (FBMNs) in the zebrafish and mouse hindbrain as a model for neuronal migrations in mammals. Previous work demonstrated that a transmembrane protein Strabismus (Stbm) was necessary for FBMN migration in zebrafish. Stbm has been well studied for its role as a component of the wingless/Wnt signaling pathway in mediating polarized cellular behaviors and patterning events in an epithelial cell layer (planar cell polarity/PCP) in flies and vertebrates. However, we have accumulated compelling preliminary evidence that, during FBMN migration, Stbm may function independently of other components of the Wnt/PCP signaling pathway. We therefore hypothesize that Stbm and Prickle1a (Pk1a), a cytoplasmic protein that potentially binds Stbm, use novel molecular and cellular mechanisms to regulate FBMN migration. We propose several approaches to uncover these mechanisms. First, the roles of various domains within Stbm, and of three genes that interact with stbm, during FBMN migration in zebrafish will be studied using gain- and loss-of-function approaches. Next, the identity of the cell type(s) in which Stbm and Pk1a functions are necessary for FBMN migration will be determined using loss-of-function and cell transplantation methods. Finally, the roles of Stbm and other PCP components in FBMN migration in mouse will be evaluated through detailed phenotypic analyses of mutant mice.
The proposed studies of neuronal migration have two-fold significance. 1) Many human neurological disorders result from defective neuronal migration. Therefore, it is essential to understand the underlying mechanisms so that the causes of and potential remedies for these diseases can be identified. 2) An ongoing challenge in stem cell research is to understand how stem cell-derived neurons can be induced to migrate accurately into brain regions damaged by injury or disease. Our studies can therefore impact efforts to increase the efficacy of stem cell therapies to treat neuronal injury and disease.
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