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The Influence of Intrinsic and Extrinsic Factors on Neurogenesis
Uniformed Services University Of The Health Sciences Bethesda United States
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Neurogenesis is a complex process through which new neurons are generated. The process is regulated by combination and coordination of cell intrinsic and extrinsic factors. I analyzed the expression and molecular function of an intrinsic factor, the nuclear regulatory protein A U-rich element-binding factor 1 AUF1 in the developing and adult brain, and the role of an extrinsic factor, the vascular endothelial growth factor VEGF and its receptor Flk1 inmediating de novo neurogenesis in the injured adult brain. The AUF1 is a known regulator of messenger RNA stability and also acts as a transcription factor upon binding to AT-rich DNA elements. Here I show that AUF1 is specifically expressed in subsets of proliferating neural precursors and differentiating postmitotic neurons of the developing cerebral cortex. Importantly, AUF1 was coexpressed with histone deacetylase 1 HDAC1 and metastasis-associated protein 2 MTA2, members of the nucleosome remodeling and histone deacetylase complex. AUF1 specifically and simultaneously bound to HDAC1, MTA2, and an AT-rich DNA element. These interactions have functional significance because AUF1s gene regulatory function was modulated by the extent of histone acetylation and, in cells lacking AUF1, the composition of the complex was modified. AUF1was also expressed in de novo neurons in the adult dentate gyrus DG. In AUF1 mutant animals, the size and cytoarchitecture of the DG were altered and the number of proliferating cells in the DG was reduced, suggesting that AUF1 is a regulator of neurogenesis both in the developing and adult brain.
APPROVED FOR PUBLIC RELEASE