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，即侧脑室的脑室下区（SVZ）和海马齿状回（DG）的颗粒下区（SGZ），新生神经元的连续产生贯穿整个生命过程。啮齿类动物的行为研究表明，海马神经发生可能在认知中起着关键作用。此外，成年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中存在的不同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，BMP信号传导的抑制已经显示出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的行为知之甚少。最近的数据表明，BMP信号可能是通过与β 1-整联蛋白，细胞外基质相互作用的蛋白质，已涉及在维护神经干细胞的相互作用进行修改。因此，该建议将测试的假设，B1-整联蛋白调节BMP信号在成年海马，这种相互作用是至关重要的NSC池的维护，从而确保整个成年期持续的神经发生。第一个具体的目标将是确定在成年DG的神经干细胞和祖细胞中1-整合素信号传导如何与BMP信号传导通路相互作用。将分析β 1-整联蛋白消融对成人DG中BMP信号传导水平的影响，并使用成人海马神经球进行体外研究，以研究β 1-整联蛋白可能调节BMP信号传导的潜在机制，包括调节BMP受体定位于脂筏。第二个具体目标将是确定B1-整联蛋白在调节成年DG中NSC更新和细胞命运中的作用。有条件的1-整联蛋白基因敲除小鼠将用于研究B1-整联蛋白缺失对DG中NSC增殖和分化的影响，以及B1-整联蛋白基因敲除对DG中NSC增殖和分化的潜在影响。 将研究β 1-整联蛋白和BMP信号传导之间相互作用的功能意义。拟议的研究将有助于确定调节成人大脑中内源性NSC行为的分子机制，并可能为促进疾病状态下海马神经发生的潜在治疗策略提供见解。

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.