REGULATION IN MAMMALIAN NEURAL PROGENITOR CELLS

描述(申请人提供)：本申请的长期目标是了解哺乳动物大脑皮层中神经前体细胞的生长和维持、分化和迁移的控制机制。在发育过程中，大脑皮层的神经元由神经上皮中的神经前体细胞产生，也称为脑室区。神经前体细胞最初在脑室区域内生长。随着皮质生成的进行，它们分化成神经元，神经元从脑室区域迁移到皮质板中的最终驻留。在皮质生成的发育过程中，生长和分化的决定是如何做出的，在很大程度上是未知的。我们的初步研究发现，eaffin-B反向信号通路是调节这一选择点的候选系统。Ephin-B是Eph受体酪氨酸激酶的跨膜配体。Ephs和Ephs的不同之处在于，它们在许多细胞-细胞相互作用中介导双向信号--Ephs是典型的正向信号，而Ephs则是独特的反向信号。在发育中的小鼠大脑皮层中，eaffin-B1及其下游信号效应蛋白PDS-RGS3在神经前体细胞中特异性地共表达。阻断ewitin-B1的表达会导致受影响的神经前体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研究神经前体细胞中这种新的控制机制。本研究的具体目的包括：(1)研究小鼠大脑皮层中与神经前体细胞相关的EphB受体及其同源受体的时空表达模式；(2)明确ePhin-B1在生长和分化中的作用，并确定反向信号通路在该功能中的作用；以及(3)研究在神经前体细胞中控制ePhin-B1表达的机制。这些研究有望帮助我们了解大脑皮层的发育，并有助于提高在细胞替代治疗中使用神经前体/干细胞的有效性。

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.