AXON GUIDANCE IN THE SPINAL CORD

本研究的目的是了解脊髓背侧互交多巴神经元轴突从脊髓背中线向脊髓腹侧转移的细胞和分子机制。最近的研究提供了证据，表明由顶板发出的化学驱避信号有助于相互联系生长锥的初始寻路。此外，我们已经确定了一种候选的趋化剂，该趋化剂是一大类分泌生长因子家族的第一个成员，骨形态发生蛋白（bone morphogenetic proteins， BN）将被确定为发育中的中枢神经系统中的扩散轴突引导信号。因此，顶板信号可能被介导为骨形态发生蛋白（BMP），其本身是转化生长因子（tgf - β）家族的成员。本实验旨在扩展顶板对共生生长锥定向的细胞分析，在体内识别顶板信号，阐明bmp作用于共生生长锥的机制。实验将解决：体外BMP活性对顶板活性的要求，发育中的小鼠脊髓背交轴突在体内方向上BMP信号的要求，使用编码BMP在顶板表达的基因被灭活的小鼠。此外，BMP家族成员在轴突引导中的作用代表了一种以前未被认识到的功能，并可能通过一种新的转导途径起作用。因此，我们将研究由共生生长锥表达的受体，并确定它们是否对轴突对bmp的打印反应是必需的。最后，我们将研究连接BMP7信号和生长锥细胞骨架的细胞内信号。通过这类新的引导分子了解化学排斥的细胞基础将阐明生长锥定向的细胞机制和tgf - β家族成员的一些广泛细胞作用的基础。

The goal of our work is to understand the cellular and molecular mechanism by which the axons of commissural dopar neurons in the dorsal spinal cord are guided away from the dorsal midline and towards ventral spinal cord. ( treats recent studies have provided evidence that chemorepellent signalling by the roof plate contributes to the initial pathfinding of commissural growth cones. Furthermore, we have identified a candidate chemorepellent that group neurorepresent the first member of a large family of secreted growth factors, the bone morphogenetic proteins (BN will be identified as a diffusible axon guidance signal in the developing CNS. Thus, the roof plate signal may be mediated to be a bone morphogenetic protein (BMP), itself a member of the transforming growth factor beta (TGF-beta) family. The experiments described here aim to extend the cellular analysis of commissural growth cone orientation by the roof plate, identify the roof plate signal in vivo and elucidate the mechanisms by which BMPs acts on commissural growth cones. Experiments will address: the requirement for BMP activity for the activity of the roof plate in vitro, the requirement for BMP signaling in the orientation in vivo of dorsal commissural axons in the developing mouse spinal cord, using mice in which the genes encoding Bmps expressed in the roof plate l been inactivated. In addition, however, a role for members of the BMP family in axon guidance represents a over previously unappreciated function and possibly acts through a novel transduction pathway. We will therefore once the receptors expressed by commissural growth cones and determine whether they are required for the axon orinting response to BMPs. Finally we will examine the intracellular signals that link BMP7 signaling to the cytoskeleton of the growth cone. Understanding the cellular basis for chemorepulsion by this novel class of guidance molecules will elucidate both the cellular mechanisms of growth cone orientation and the basis of some of the wide rang neur' cellular actions of members of the TGF-beta family.