REGULATION IN MAMMALIAN NEURAL PROGENITOR CELLS

描述（由申请人提供）：本申请的长期目标是了解控制哺乳动物大脑皮层中神经祖细胞生长和维持、分化和迁移的机制。在发育过程中，大脑皮层的神经元由神经上皮（也称为脑室区）中的神经祖细胞产生。神经祖细胞最初生长在心室区。随着皮质发生的进行，它们分化为神经元，这些神经元从心室区迁移到它们在皮质板中的最终住所。在皮质发生的发育过程中，生长与分化是如何决定的，这在很大程度上是未知的。我们的初步研究确定了ephrin-B反向信号通路作为调控这一选择点的候选系统。Ephrin-B是Eph受体酪氨酸激酶的跨膜配体。ephrin和Ephs的独特之处在于它们在许多细胞-细胞相互作用中介导双向信号——一个典型的正向信号由Ephs传递，一个独特的反向信号通过ephrin传递。在发育中的小鼠大脑皮层中，ephrin-B1及其下游信号效应蛋白PDS-RGS3在神经祖细胞中特异性共表达。阻断ephrin-B1表达导致受影响的神经祖细胞向外迁移到皮质板，这很可能是分化的结果。目前的研究将进一步探讨这种新的神经祖细胞控制机制。具体目的包括：(1)表征ephrin- b及其同源EphB受体在小鼠大脑皮层神经祖细胞中的时空表达模式；(2)明确ephrin-B1在生长和分化中的作用，并确定反向信号通路在ephrin-B1这一功能中的作用；(3)研究神经祖细胞中ephrin-B1表达的调控机制。这些研究有望有助于我们对大脑皮层发育的理解，并有助于提高神经祖细胞/干细胞在细胞替代疗法中的有效性。

DESCRIPTION (provided by applicant): The long-term objective of this application is to understand the mechanisms that control the growth and maintenance, differentiation, and migration of neural progenitor cells in the mammalian cerebral cortex. During development, neurons of the cerebral cortex arise from neural progenitor cells in the neuroepithelium, also called the ventricular zone. Neural progenitor cells initially grow within the ventricular zone. As corticogenesis proceeds, they differentiate into neurons, which migrate out of the ventricular zone into their final residence in the cortical plate. How the decision of growth vs. differentiation is made during this developmental progression of corticogenesis is largely unknown. Our preliminary studies identified the ephrin-B reverse signaling pathway as a candidate system in regulation of this choice point. Ephrin-B is the transmembrane ligand of the Eph receptor tyrosine kinases. Ephrins and Ephs are distinctive in that they mediate bi-directional signaling in many cell-cell interactions-a typical forward signal by Ephs and a unique reverse signal through ephrins. In the developing mouse cerebral cortex, ephrin-B1 and its downstream signaling effector protein PDS-RGS3 are specifically co-expressed in neural progenitor cells. Blocking ephrin-B1 expression results in outward migration of the affected neural progenitor cells into the cortical plate, most likely as a result of differentiation. The current study will further investigate this novel mechanism of control in neural progenitor cells. The specific aims include: (1) characterize the temporal and spatial expression patterns of ephrin-Bs and their cognate EphB receptors in relation to neural progenitor cells in the mouse cerebral cortex; (2) define the role of ephrin-B1 in growth vs. differentiation, and determine the contribution of the reverse signaling pathway in this function of ephrin-B1; and (3) investigate the mechanisms that control the expression of ephrin-B1 in neural progenitor cells. These studies are expected to contribute to our understanding on the development of the cerebral cortex and should help in improving the effectiveness of using neural progenitor/stem cells in cell replacement therapy.