Molecular regulation of neural stem cells and activity-dependent neurogenesis in the adult brain.

摘要

Neural stem cells (NSCs) are present in adult mammalian brains and continually generate neurons throughout life. Strategic activity-dependent addition of new neurons to the existing circuitry represents a prominent form of structural plasticity and contributes to specific types of learning and memory. Molecular mechanisms regulating adult NSCs and subsequent activity-dependent neurogenesis are foci of this thesis research.;The first part of the thesis addresses mechanisms through which adult NSC identity is maintained by fibroblast growth factor (FGF)-2 signaling Molecular genetic manipulation reveals essential roles of MAPK in both promoting self-renewal and suppressing neuronal differentiation of adult NSCs. Clustered presentation of FGF-2 enables a switch-like MAPK activation and cellular self-renewal, demonstrating the impact of local FGF-2 presentation on adult NSC behavior.;The second part of the thesis addresses regulatory mechanisms through which adult NSC identity is reprogrammed into pluripotency. Using a novel double fluorescent reporter system to monitor and quantitatively analyze transient early reprogramming events, we found that a pair of histone-modifying enzymes (G9a and Jhdm2a) regulates the reverting of adult NSCs into pluripotency. Our results suggest that reprogramming occurs with coordinated actions between erasure of somatic epigenome and transcriptional resetting to restore pluripotency.;The third part of the thesis addresses extrinsic mechanisms that electrical activity promotes adult neurogenesis from adult NSCs. Neuronal activity induces robust NMDAR-dependent expression of Gadd45b in mature dentate granule cells in vivo. Adult Gadd45b-KO mice exhibit specific deficits in activity-induced proliferation of adult NSCs and dendritic development of newborn neurons. Mechanistically, Gadd45b is required for activity-induced 5-methylcytosine demethylation of promoters and expression of corresponding genes that are critical for adult neurogenesis, including BDNF and FGF. Thus, Gadd45b links circuit activity to epigenetic DNA modification in mature neurons, which in turn controls the expression of key extrinsic niche factors for regulation of adult NSCs and their development.;In summary, these studies have led to novel understanding on how adult NSCs are maintained, reprogrammed in culture, and differentiated into new neurons in response to neuronal activity in the adult brain, and have significant implications for therapeutic application of adult NSCs and functional roles of activity-dependent adult neurogenesis.