Integrin/ECM gating of adult neural stem cell activity

描述（由申请人提供）：整合素及其与细胞外基质蛋白（ECM）的相互作用调节许多细胞过程，但其在神经干细胞生物学中的作用尚不明确。在这里，我们关注一种新的整合素- ecm相互作用，它为成人大脑中的干细胞自我更新和神经发生定义了一个允许的环境。神经干细胞持续存在于成年哺乳动物的大脑中，并支持神经元和神经胶质的持续产生。尽管胶质细胞在大脑的所有区域都能产生，但原生神经发生仅限于脑室下区（SVZ）和海马颗粒下区（SGZ）。神经新生可以在大脑的其他区域触发，比如受伤，但新神经元的产生和保留是低效的，充其量只能说是失败的。更好地了解自然支持干细胞库维持的局部环境，以及它们在神经发生中的有效利用，可能会导致神经修复/再生方面的重大进展。为此，我们已经确定了几种整合素- ecm相互作用，这些相互作用选择性地定位于大脑的原生神经源区域。在体外，我们发现这些相互作用限制了神经干细胞和祖细胞对有丝分裂原的反应，在这里，我们建议研究确定成人神经源性生态位中使用的具体机制，以：1)维持和调节干细胞自我更新和干细胞池大小；2)调节新生神经母细胞的瞬时扩增和存活；3)在体育锻炼或学习经历后，介导控制海马神经发生的生理信号。

DESCRIPTION (provided by applicant): Integrins and their interactions with extracellular matrix proteins (ECM) regulate many cellular processes but their role in neural stem cell biology is poorly defined. Here we focus on a novel integrin-ECM interaction that defines a permissive environment for stem cell self-renewal and neurogenesis in the adult brain. Neural stem cells persist in the adult mammalian brain and support the continuing production of neurons and glia. Although glia are produced in all areas of the brain, native neurogenesis is restricted to the subventricular zone (SVZ) and hippocampal subgranular zone (SGZ). Neurogenesis can be triggered in other areas of the brain, for example by injury, but the production and retention of new neurons is inefficient and abortive at best. A better understanding of local environments that naturally support the maintenance of a stem cell pool as well as their efficient use in neurogenesis could lead to significant advances in neural repair/regeneration. Toward this end, we have identified several integrin-ECM interactions that are selectively localized to the native neurogenic areas of the brain. In vitro, we show that these interactions gate neural stem and progenitor cell response to mitogens and here we propose studies to define the specific mechanisms used within the adult neurogenic niche to: 1) maintain and regulate stem cell self-renewal and stem cell pool size; 2) regulate the transient amplification and survival of newly generated neuroblasts; and 3), mediate physiological signaling that controls hippocampal neurogenesis in response to physical exercise or learning experiences.