The continuous generation of new neurons occurs throughout life in two localized regions of the adult mammalian brain, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. Behavioral studies in rodents have suggested that ongoing hippocampal neurogenesis may play a key role in cognition. Further, impairments in adult hippocampal neurogenesis have been linked to multiple disease states, including Alzheimer's disease and depression. Diverse signaling molecules present in the SGZ regulate multiple aspects of the neurogenic process, including neural stem cell (NSC) maintenance, proliferation, and differentiation. In particular, inhibition of BMP signaling has been shown to promote hippocampal neurogenesis and improve cognition. However, relatively little is known about how different signaling pathways may interact to regulate NSC behavior. Recent data suggests that BMP signaling may be modified by interaction with ?1-integrin, an extracellular matrix-interacting protein that has been implicated in maintenance of NSCs. This proposal will therefore test the hypothesis that B1-integrin modulates BMP signaling in the adult hippocampus and that this interaction is critical for maintenance of the NSC pool, thereby ensuring ongoing neurogenesis throughout adulthood. The first specific aim will be to determine how ?1-integrin signaling interacts with the BMP signaling pathway in neural stem and progenitor cells of the adult DG. The effects of ablation of ?1-integrin on the level of BMP signaling in the adult DG will be analyzed and in vitro studies using adult hippocampal neurospheres will be performed to investigate potential mechanisms by which B1-integrin may modulate BMP signaling, including regulation of the localization of BMP receptors to lipid rafts. The second specific aim will be to define the role of B1-integrin in regulating NSC renewal and cell fate in the adult DG. Conditional ?1-integrin knockout mice will be used to investigate the effects of loss of B1-integrin on NSC proliferation and differentiation in the DG and the potential functional significance of the interaction between ?1-integrin and BMP signaling will be investigated. The proposed studies will help define the molecular mechanisms that regulate the behavior of endogenous NSCs in the adult brain and may provide insight into potential therapeutic strategies for promoting hippocampal neurogenesis in disease states.
Throughout life, new neurons are continuously being generated in the hippocampus, a region of the brain that is critical for learning, memory, and regulation of emotion. The goal of this proposal is to understand the factors that regulate the ability of stem cells in the hippocampus to divide and generate new cells throughout adulthood. Successful completion of this work could lead to the identification of therapeutic targets for restoring cognition in patients with diseases involving impaired hippocampal function.