Almost all neurons in the vertebrate brain are foreign born - that is, they are born at or near the ventricular surface and then migrate to another location where they make their connections and carry out their specialized functions. Neuronal migrations can be radial, parallel to the api- co-basal axis of the neuroepithelium, or they can be tangential: orthogonal to the apical-basal axis - i.e., in the plane of the neuroepithelium. With te goal of discovering genetic mechanisms regulating directed neuronal migration, we have established the facial branchiomotor neurons (FBMNs; cranial nerve VII), which undergo a stereotyped and evolutionarily conserved tangen- tial migration from hindbrain rhombomere (r)4 to r6, as a model system in our lab. Forward ge- netic screens in our lab and others have identified multiple core components of the Planar Cell Polarity (PCP) pathway as being essential for FBMN migration. The PCP pathway is best under- stood as a cell contact-dependent molecular mechanism for generating and transmitting polarity between cells in the plane of an epithelium. However PCP has been implicated in a growing number of cell migrations during development and disease states. Currently no coherent model exists for how PCP regulates directional cell migration. This is mainly because the polarized cell- cell interactions that defin PCP are difficult to reconstitute in cell culture; we must therefore attack the problem in vivo. Th zebrafish model, with its exquisite live imaging, facile transgen- esis and powerful forward and reverse genetics tools, affords us this opportunity. We hypothe- size that direct PCP signaling between the planar-polarized cells of the neuroepithelium and the motile FBMNs polarizes FBMN protrusive activity in the direction of migration. We pro- pose to test the predictions of thi model first by identifying the cells in the migratory environ- ment that are responsible for directing migration (Aim 1), and then by elucidating how PCP sig- naling within the FBMNs affects their behavior in vivo (Aim 2). Furthermore in Aim 2 we will discover how interactions between migrating FBMNs and the surrounding neuroepithelium in- fluence PCP protein localization and protrusive activity in the FBMNs. Finally, we propose to enrich our understanding of PCP-dependent neuron migration through the cloning of FBMN migration mutants we have identified in a forward genetic screen (Aim 3).
We propose to study a fundamental problem in the early development of the vertebrate brain: how neurons migrate from their place of birth at the inner surface of the brain to the place where they make their connections and carry out their functions. This is an important question for two reasons. First, many human neurodevelopmental disorders are the result of aberrant or failed neuron migration. Second, the particular pathway whose role in neuron migration we propose to study, the planar cell polarity pathway, is associated with human neurodevelopmental disorders including spina bifida and ciliopathies.
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