The overall goal of the present work is to characterize the cell and molecular mechanisms that regulate neural and vascular cell interactions during development. The central objective of this work is to determine the role of vascular endothelial growth factor (VEGF) in regulation of neurogenesis. Results from the proposed study will impact our understanding of the development of the central nervous system (CNS) as well as the plasticity of the CNS in response to mechanical injury or pathologic stress. Neural and vascular systems develop in concert and several factors have been identified with overlapping function in the two systems. An emerging model of neural and vascular system interdependence includes the potent angiogenesis factor, VEGF, and its dual role as a neural regulator. The angiogenesis-inducing effects of VEGF are largely mediated via activation of the VEGF receptor-2 (VEGFR2) homodimer that can use the co-receptor, neuropilin 1. Neuropilin 1 plays a critical role in mediating axon guidance cues, but can also contribute to angiogenesis via its association with VEGFR2. VEGF is expressed predominantly as three isoforms in the mouse, VEGF120, VEGF164 and VEGF188. Results from homologous recombination studies in mice have led to the suggestion of distinct roles for the different VEGF isoforms. The isoforms differ in their ability to bind to heparan sulfate proteoglycans in the matrix and on the cell surface and to interact with the neuropilin 1 co-receptor. Only VEGF164 has been shown to bind to and activate the VEGFR2/neuropilin 1 complex. VEGF164 is the predominant isoform in the brain. Although a number of studies have suggested a role for VEGF in the nervous system, little is known about the direct role that VEGF plays in neurogenesis. The hypothesis of this proposal is that VEGF regulates developmental neurogenesis via the VEGFR2-neuropilin pathway. The hypothesis will be tested with the following aims: 1) to characterize the cell-type specificity and expression patterns for VEGF, VEGFR2 and activated VEGFR2 during developmental neurogenesis in the CNS and 2) to test the role of VEGF-neuropilin signaling in developmental neurogenesis in mice lacking VEGF-neuropilin signaling. ? Project Narrative: The results from experiments described in this proposal are directly relevant to human health in the areas of brain development, function, and repair. Neuronal stem cells are the source of all brain neurons and have recently been found in the adult. Understanding how neural stem cells arise, differentiate, divide and die may be the key to finding out how to restore brain function after debilitating CNS injuries such as stroke, lesion, and neurodegenerative disease. ? ? ?
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| Darland, Diane C; Cain, Jacob T; Berosik, Matthew A et al. (2011) Vascular endothelial growth factor (VEGF) isoform regulation of early forebrain development. Dev Biol 358:9-22 |
