AXON GUIDANCE IN THE SPINAL CORD

我们的工作的目标是了解的细胞和分子机制，其中连合dopar神经元的轴突在脊髓背侧中线，并向腹侧脊髓引导。最近的研究提供了证据表明，顶板的化学排斥信号有助于连合生长锥的最初寻路。此外，我们已经确定了一种候选的化学排斥剂，该化学排斥剂代表了分泌生长因子大家族的第一个成员，骨形态发生蛋白（BN）将被确定为发育中CNS中的可扩散轴突引导信号。因此，顶板信号可以被介导为骨形态发生蛋白（BMP），其本身是转化生长因子β（TGF-β）家族的成员。这里描述的实验的目的是延长连合生长锥方向的顶板的细胞分析，确定在体内的顶板信号，并阐明骨形态发生蛋白作用于连合生长锥的机制。实验将解决：体外顶板活性对BMP活性的要求，发育中的小鼠脊髓中背连合轴突体内定向对BMP信号传导的要求，使用编码在顶板中表达的BMP的基因被失活的小鼠。然而，此外，BMP家族成员在轴突导向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，我们将研究连合生长锥表达的受体，并确定它们是否是轴突对BMP的定向反应所必需的。最后，我们将研究连接BMP 7信号到生长锥细胞骨架的细胞内信号。了解这类新型导向分子的化学排斥的细胞基础将阐明生长锥取向的细胞机制和TGF-β家族成员的一些宽范围神经细胞作用的基础。

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.