The Neurogenins (Ngns) are basic-helix-loop-helix (bHLH) transcription factors that regulate cell fate determination in the developing brain. Ngns control the generation of committed neural progenitors from multipotent stem cells, but also play a key role in the decision of committed neural progenitors to become neurons or astrocytes. Our laboratory has found that Ngns control this critical cell fate decision in two ways; by activating a neuronal differentiation program and by inhibiting the process of astrocyte differentiation. The objective of the experiments proposed in this application is to gain a more thorough understanding of the multiple functions of Ngns in cell fate determination. Specifically, we plan to elucidate the molecular mechanisms by which Ngns act and to determine how Ngn action is regulated by extracellular factors during development. Our preliminary findings indicate that Ngn forms a complex with, and is phosphorylated by, Erk1, a component of the Ras/Erk signaling pathway. We hypothesize that extracellular factors expressed in the developing cortex, act via the Ras/Erk signaling pathway to regulate Ngn's ability to induce neurogenesis and inhibit astrocyte differentiation. To begin to address this hypothesis we propose the following specific aims: 1) To investigate the role of Ras/Erk signaling in the control of Ngn activity. By characterizing the effects of Erk-dependent phosphorylation on Ngn function, we hope to gain an understanding of the interplay between extrinsic factors and intrinsic transcriptional regulators in the control of nervous system development. 2) To identify Ngn target genes in the developing cortex. This information will provide insight into the mechanisms by which Ngns promote cortical development and will serve as a basis for investigating how extracellular factors acting through intracellular signaling pathways regulate Ngn activity. It is our hope that the proposed experiments will enhance our understanding of Ngn function, give insight into the mechanisms of cell fate determination and differentiation, and generate new opportunities for the development of therapeutic strategies to combat a variety of developmental and neurodegenerative diseases.
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