The Role of Filamin in Periventricular Heterotopias

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DESCRIPTION (provided by applicant): Developmental disorders of the human cerebral cortex comprise 15-40 percent of epilepsy cases, most notably intractable pediatric seizures. These disorders have deleterious affects on both the psychological and physical well being of individuals. Identification of the causative genes and characterization of their function will provide necessary insight into the neuropathology of epilepsy as well as extend the current understanding of normal cortical development. Through such a genetic approach, recent findings have shown that mutations in the actin-binding protein filamin I (FLN1) are implicated in the human x-linked disorder, periventricular heterotopia and epilepsy (PVH). This neurogenetic disorder is characterized by the failure of subsets of neurons to migrate from the ventricle during corticogenesis, in association with thinning of the corpus callosum and cerebellar hypoplasia. While the filamin proteins are known to regulate cell stability, protrusion and motility across various biologic systems, their potential functions within the central nervous system has only just come to light with the recent association of FLNI to PVH. Thus, the overall goal of this proposal is to analyze the roles of FLN1 and a highly homologous protein, FLN3, in relation to neurogenesis, neuronal migration, and subsequent differentiation. Specific Aim 1 will characterize the temporal and spatial pattern of filamin protein and mRNA expression, to test the hypothesis that the actin-binding proteins localize to appropriate neuronal populations during periods of ongoing cortical neurogenesis, migration and axonal outgrowth. Specific Aim 2 will identify protein-protein interactions between FLN1, FLN3 and other novel and known developmental genes, to test the hypothesis that filamin proteins are involved in signal transduction pathways essential to cortical development. Specific Aim 3 will directly evaluate the functional significance of such interactions through generation of dominant-negative and overexpression constructs. FLN1 mutant mice will also provide an animal model with which to study filamin interactions during the various stages of neuronal development. The candidate has completed training in both medical and graduate programs. His residency training is in Neurology, and he earned his doctoral degree in Neuroscience studying neocortical transplantation paradigms in effecting neuronal specification, migration and directed differentiation during both cortical development and following targeted neuronal degeneration. He now seeks further training under the mentorship of Dr. Chris Walsh, whose research interests center on genetic approaches toward understanding fundamental mechanisms governing development of the cerebral cortex. It is the candidate's intention to combine these newly acquired molecular and genetic approaches with his prior training in transplantation to pursue an academic career in Neurology and the Neurosciences, primarily in the field of cortical development and malformations as they pertain to epilepsy.