Transcriptional Control of Terminal Differentiation

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DESCRIPTION (provided by applicant): The linkage between cell cycle exit and terminal differentiation represents a critical phase of cellular development. However, very little is known regarding the mechanisms functioning at the growth arrest/differentiation interface in neurons and other cell types. Such mechanisms are likely to play a vital role in not only the onset or establishment of terminal differentiation, but also in the maintenance of its normal irreversibility. Thus, elucidating the mechanisms operating at this critical developmental juncture is also likely to be importance in understanding the etiology and treatment of many forms of cancer. The long-term goal of this proposal is to determine how the events associated with growth arrest are mechanistically linked to transcriptional regulation of specific genes during onset of terminal differentiation and how transcription factors activating these promoters are themselves regulated by growth arrest signals. This proposal focuses on neurogenesis, during which arrest of neuroblasts leads to the "birth" of postmitotic neurons and the onset of terminal differentiation. This event is a major determinant of which neurons survive and ultimately form the complex wiring of the nervous system, and also is important in establishing the identities of specific neuronal sub-types. An underlying hypothesis is that the mechanisms linking growth arrest and differentiation in neurons are cell lineage-specific. A major goal is to characterize the basis for this neuron-specificity and, in particular, the nature of the regulatory transcription factors involved. These studies will help to reveal the mechanisms controlling neurogenesis during development as well as in the adult nervous system, and in this regard are relevant to potential therapies for neuro-degenerative diseases. Further, they are important for understanding tumorigenesis in general, including neoplasias of the nervous system.