Bidirectional Tyrosine Kinase Signaling

摘要 海马体是大脑中维持增殖供应的两个主要区域之一 能够在成年后产生新神经元的细胞。在这里，自我更新的茎和 海马齿状回颗粒下带(SGZ)的瞬时扩增祖细胞 脑回(DG)分裂，短距离迁移，并分化为新的颗粒细胞神经元， 整合到大脑现有的回路中。尽管人们认为新的神经元产生了 可能参与学习和记忆，这是调节干细胞/祖细胞迁移的因素， 增殖、分化以及最终的突触整合到大脑中都不是很好 明白了。EphB1和EphB2受体酪氨酸激酶在海马区的表达 胚胎和出生后发育以及成人大脑中的干细胞/祖细胞。 利用基因靶向小鼠进行的体内研究表明，EphB1的缺失和更深刻的 EphB1+EphB2导致巢蛋白阳性的干/祖细胞数量减少， 填充正在开发的DG。确实设法填充DG的突变干细胞/祖细胞 显示细胞突起的极性有缺陷，细胞体位于细胞突起外 SGZ生态位正常，增殖增加。我们的数据导致了这样的假设，即 EphB受体与其同源的Ephin-B跨膜配体相互作用，转导 重要信号进入海马干/祖细胞控制其迁移 随着DG的形成而发展，并在成年后随着SGZ的继续发展而发展 新生神经元。为了进一步检验我们的想法，我们将：(1)确定细胞内信号 EphB受体控制干细胞/祖细胞迁移的机制 和(2)使用条件策略删除EphB受体在 成熟海马区的干细胞/祖细胞，以确定这些分子如何 可能调节成神经细胞的行为，特别是在成人大脑中。拟议的研究将 对干细胞生物学和细胞与细胞的相互作用有更全面的了解 正在发挥作用的生化信号。预计这项工作将取得进展。 在我们对调节正常人神经发生的信号机制的理解中 大脑。这可能会对我们学习和学习能力背后的分子基础提供重要的洞察 存储记忆。最后，由于对海马体的损伤和干细胞的相关变化 增殖/迁移可由多种病理因素引起，拟议的研究还可能 为未来的干细胞治疗提供新的分子靶点 神经性疾病、变性或损伤。叙述性 海马体是大脑中参与学习和记忆的主要中心，是 成人大脑中包含干细胞的两个区域。建议的研究集中在 海马区干细胞上表达的EPH受体酪氨酸激酶及其功能 传递对正常干细胞迁移和 增殖模式。预计这项研究将在我们的 了解发育中和成人脑中干细胞的分子调控， 并可能提供对我们如何学习和存储记忆的洞察。此外，由于对 海马体可以导致干细胞增殖的变化，拟议的研究可能 也为未来治疗个体的干细胞疗法提供了新的分子靶点 神经衰弱的患有神经系统疾病、退化或损伤的

Abstract The hippocampus is one of two major areas in the brain that maintains a supply of proliferating cells that are able to produce new neurons well into adulthood. Here, self-renewing stem and transient-amplifying progenitor cells in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) divide, migrate a short distance, and differentiate into new granule cell neurons that integrate into the existing circuitry of the brain. Although it is thought the new neurons generated may participate in learning and memory, the factors that regulate stem/progenitor cell migration, proliferation, differentiation, and eventual synaptic integration into the brain are not well understood. The EphB1 and EphB2 receptor tyrosine kinases are expressed in hippocampal stem/progenitor cells during embryonic and postnatal development as well as in the adult brain. In vivo studies using gene targeted mice show that deletion of EphB1 and more profoundly EphB1+EphB2 results in a reduced number of nestin-positive stem/progenitor cells that populate the developing DG. Mutant stem/progenitor cells that do manage to populate the DG exhibit defective polarity of cell processes, ectopic positioning of cell bodies outside of the normal SGZ niche, and increased proliferation. Our data leads to the hypothesis that, upon interaction with their cognate ephrin-B transmembrane ligands, the EphB receptors transduce important signals into hippocampal stem/progenitor cells to control their migration during development as the DG forms and later during adulthood as the SGZ continues to give rise to newborn neurons. To further test our ideas we will: (1) determine the intracellular signaling mechanisms that EphB receptors use to control the migration of stem/progenitor cells during development of the hippocampus, and (2) use conditional strategies to delete EphB receptors in stem/progenitor cells of the mature hippocampus in order to determine how these molecules may regulate neuroblast behaviors specifically in the adult brain. The proposed research will provide a better general understanding of stem cell biology and the cell-cell interactions and biochemical signals that are at play. It is further anticipated that this work will lead to advances in our understanding of the signaling mechanisms that regulate neurogenesis in the normal brain. This may provide important insight into the molecular basis behind our ability to learn and store memories. Finally, as damage to the hippocampus and associated changes in stem cell proliferation/migration can result from numerous pathologies, the proposed research may also provide novel molecular targets for future stem cell therapies to treat individuals suffering from neurological diseases, degeneration, or injury. Narrative The hippocampus is a major center of the brain involved in learning and memory and is one of the two areas in the adult brain that contain stem cells. The studies proposed focus on Eph receptor tyrosine kinases which are expressed on hippocampal stem cells and function to transduce chemical signals that are important for normal stem cell migration and proliferation patterns. It is anticipated this research will lead to advances in our understanding of the molecular regulation of stem cells in the developing and adult brain, and may provide insight into how we learn and store memories. Furthermore, as damage to the hippocampus can lead to changes in stem cell proliferation, the proposed research may also provide novel molecular targets for future stem cell therapies to treat individuals suffering from neurological diseases, degeneration, or injury.