Neuregulins in Adult Neurogenesis and Migration

描述（由申请人提供）：在这个项目中，我们建议研究酪氨酸激酶受体ErbB4的一种异构体及其配体神经调节蛋白（NRGs）在形成吻侧迁移流（RMS）的成人神经发生和细胞迁移中的作用。在成年小鼠中，出生在侧脑室前区（SVZ）的神经祖细胞作为RMS中的神经元链迁移到嗅球，并在嗅球中分化为中间神经元。ErbB4受体在RMS中显著表达，而NRGs的所有亚型都在RMS周围的嗅觉和皮层结构中表达。在体外实验中，NRG-1似乎可以阻断迁移神经元链的形成，并分散已经形成的链。另一方面，NRG-2在体外和体内诱导神经发生，表明其招募增殖机制。本研究拟通过在成年小鼠前脑室注入重组NRG来阐明ErbB4受体在SVZ和RMS神经发生和细胞迁移中的作用。然后，我们提出在成年小鼠的SVZ和RMS中表征受ErbB4激活影响的细胞类型。最后，我们建议使用实时成像和固定组织分析来确定RMS中迁移神经母细胞对ErbB4激活和失活的反应在速率、组织和方向上的潜在变化。通过这些努力，我们希望对成人大脑中调节神经祖细胞增殖、迁移和分化的分子机制有更好的了解

DESCRIPTION (provided by applicant): In this project, we propose to study the role of one isoform of the receptor tyrosine kinases, ErbB4, and its ligands, the neuregulins (NRGs), in adult neurogenesis and migration of cells that form the rostral migratory stream (RMS). In adult mice, neural progenitor cells born in the anterior region of the lateral ventricle (SVZ) migrate as chains of neurons in the RMS to the olfactory bulb where they differentiate into interneurons. The ErbB4 receptor is prominently expressed in the RMS while all isoforms of NRGs are expressed in olfactory and cortical structures in the immediate surroundings of the RMS. In vitro, NRG-1 appears to block the formation of chains of migrating neurons and disperses chains that have already formed. NRG-2, on the other hand, induces neurogenesis in vitro and in vivo, suggesting that it recruits proliferative mechanisms. Here we propose to elucidate the role of the ErbB4 receptor in neurogenesis and migration of cells in the SVZ and RMS by infusing recombanant NRG's in the anterior ventricles of adult mice. We then propose to characterize the cell types affected by ErbB4 activation in the SVZ and RMS of adult mice. Finally, we propose to identify potential changes in rate, organization, and orientation of migrating neuroblasts in the RMS in response to ErbB4 activation and inactivation using real-time imaging as well as fixed tissue analyses. Through these efforts, we hope to gain an improved understanding of molecular mechanisms that regulate neural progenitor cell proliferation, migration and differentiation in the adult brain