While transcription factors of the Nuclear Factor One (NFI) family are critical for many aspects of neural development, little is known about how they function in vivo. The goal of this research is to determine the mechanisms by which NFI factors direct the development of the basilar pons (BP) and other precerebellar nuclei. These hindbrain nuclei derive from progenitors residing in the rhombic lip,and migrate along unique pathways to their adult locations. Mice lacking the Nfia gene exhibit a moderate reduction in BP size. In Nfib knockouts, however, the BP is virtually absent, with alterations in the pontine migratory stream suggesting defects in both cell survival and cell migration. The respective phenotypes associated with Nfia and Nfib mutant mice imply that NFI-B may play a specific role in directing BP development. Alternatively, NFI factors may be functionally redundant, with overall NFI protein levels being the important determinant of BP development. To test these models of NFI action, experiments in Aim 1 will compare cell death, migration, and specification in both mutants to determine whether Nfia and Nfib regulate BP development by the same mechanisms. Experiments in Aim 2 will determine if other NFI factors can compensate for the loss of Nfib. Expression and rescue studies in Aim 3 will determine if Nfia and Nfib form a regulatory network with Pax6 and other transcription factors to control BP development;this will include the identification of downstream targets of Nfia and Nfib. These studies will address fundamental questions regarding the regulation of neural development by NFI transcription factors and the molecular mechanisms underlying the formation of the precerebellar system. Elucidating these mechanisms is critical for understanding developmental and neurological defects associated with the hindbrain and cerebellum that can lead to severe problems in motor coordination and cognition. Many birth defects and neurological disorders result from the failure of the hindbrain and cerebellum to develop correctly. Studying the molecular mechanisms of hindbrain development will lead to a greater understanding of these disorders, and identify potential therapeutic targets for their treatment.
