The major goal of this proposal is to elucidate basic cellular mechanisms of neurogenesis, and to understand the mechanisms that control the ability of neural stem cells to survive and proliferate. Proper development of the cerebral cortex is essential for normal cognitive function, and requires the precise completion of a series of developmental steps. Abnormalities of cerebral cortical development can cause mental retardation, epilepsy, learning disorders, and cerebral palsy. In the previous funding period of this grant we studied of the mechanisms of several causes of microcephaly (small cerebral cortex), these studies suggest that microcephaly genes play important roles in the control of neural proliferation and, in some cases, the control of neural cell fate. In this grant we propose to analyze the stem cell niche that regulates neural stem cells in the developing, and the adult, brain. These experiments have profound significance for elucidating the fundamental control of neural stem cells in the brain, and have potential therapeutic implications in improving our ability to control these stem cells. We propose to study the regulation of neurogenesis by the embryonic cerebral spinal fluid (eCSF) proteome. Although many genes that regulate neurogenesis have been identified, the global controls that initiate and terminate neurogenesis are completely unknown. Our preliminary data suggest that eCSF, which bathes the cilia of all known neural stem cells both during development and in adulthood, shows instructive effects on neurogenesis in cortical explants and cultured neural stem cells that differ with the age of the explant, and the age of the eCSF. We propose to analyze the effects of eCSF on cerebral cortical explants in vitro and cultured neural stem cells in vitro and age-related changes in the effects of eCSF (and adult CSF) on cortical explants and cultured neural stem cells. We further propose to identify and verify eCSF components that regulate cortical neurogenesis. The pace and nature of neurogenesis changes rapidly in the last days of embryonic development suggesting that global cues change as well. Our preliminary data show that the functional effects and protein composition of CSF changes dramatically during this same time-frame. To study this we will use MALDI-mass spectroscopy and Western analysis to determine the composition of the CSF proteome during the period of cortical neurogenesis, and analyze changes in concentration of key CSF components. We will also study the regulation of neurogenesis by specific proteins of the eCSF. We have identified IGF2 as one specific growth factor that is highly expressed in eCSF during neurogenesis, and down regulated postnatally. We propose to analyze the effects of gain and loss IGF2 and other specific eCSF proteins on neurogenesis.
Proper development of the cerebral cortex (the portion of the brain that controls higher functions such as memory and consciousness) is essential for normal cognitive function, and requires the precise completion of a series of developmental steps. Abnormalities of cerebral cortical development can cause mental retardation, epilepsy, learning disorders, and cerebral palsy. The experiments proposed in this grant have profound significance for elucidating the fundamental control of neural stem cells (cells that will become neurons) in the brain, and have potential therapeutic implications in improving our ability to control these stem cells.
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|Lodato, Michael A; Woodworth, Mollie B; Lee, Semin et al. (2015) Somatic mutation in single human neurons tracks developmental and transcriptional history. Science 350:94-8|
|Johnson, Matthew B; Wang, Peter P; Atabay, Kutay D et al. (2015) Single-cell analysis reveals transcriptional heterogeneity of neural progenitors in human cortex. Nat Neurosci 18:637-46|
|Jamuar, Saumya S; Walsh, Christopher A (2015) Genomic variants and variations in malformations of cortical development. Pediatr Clin North Am 62:571-85|
|Manzini, M Chiara; Xiong, Lan; Shaheen, Ranad et al. (2014) CC2D1A regulates human intellectual and social function as well as NF-ÎºB signaling homeostasis. Cell Rep 8:647-55|
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