Beta1-integrin and BMP pathway interactions in adult hippocampal neurogenesis

描述（由申请人提供）：在成年哺乳动物大脑的两个局部区域，侧脑室的室下区（SVZ）和海马齿状回（DG）的亚颗粒区（SGZ），在整个生命过程中不断产生新的神经元。啮齿类动物的行为研究表明，正在进行的海马神经发生可能在认知中起关键作用。此外，成人海马神经发生的损伤与多种疾病状态有关，包括阿尔茨海默病和抑郁症。SGZ中存在的多种信号分子调节神经发生过程的多个方面，包括神经干细胞（NSC）的维持、增殖和分化。特别是，抑制BMP信号传导已被证明可以促进海马神经发生和改善认知。然而，对于不同的信号通路如何相互作用来调节NSC行为，人们知之甚少。最近的数据表明，BMP信号可能通过与1-整合素（一种与细胞外基质相互作用的蛋白，与NSCs的维持有关）的相互作用而改变。因此，该建议将验证b1整合素调节成人海马中BMP信号的假设，并且这种相互作用对于维持NSC库至关重要，从而确保整个成年期持续的神经发生。第一个具体目标将是确定在成年DG的神经干和祖细胞中，1-整合素信号如何与BMP信号通路相互作用。我们将分析1-整合素消融对成人DG中BMP信号水平的影响，并利用成人海马神经球进行体外研究，以研究b1 -整合素调节BMP信号的潜在机制，包括调节BMP受体在脂筏上的定位。第二个具体目标将是确定b1整合素在调节成年DG中NSC更新和细胞命运中的作用。条件1-整合素敲除小鼠将被用来研究b1 -整合素缺失对NSC在DG中的增殖和分化的影响及其潜力

DESCRIPTION (provided by applicant): 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.