AXON GUIDANCE IN THE SPINAL CORD

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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.