Mechanisms of actin regulation in synaptogenesis versus axon guidance

描述（由申请人提供）：轴突引导和突触发生代表了神经元发育中不同的生物学过程，但它们是由一组重叠的外部信号介导的，包括netrin， wnt和信号蛋白。在轴突引导中，这些线索将肌动蛋白丝（F- actin）的形成调节到生长锥的丝状延伸，而在突触发生中，它们指导F-actin在新生的突触前区域组装，以支撑突触前组装程序的招募。为了确定在指定轴突引导与突触发生时，相同的外部线索如何指导不同的肌动蛋白动力学，我们将研究秀丽隐杆线虫在这两个过程中的肌动蛋白调节机制。由于秀丽隐杆线虫是半透明的，它的轴突形态和突触模式很容易用细胞和突触特异性荧光标记观察到。此外，易于进行前向遗传筛选，结合大量可用的特征突变体，使秀丽隐杆线虫成为研究神经元发育的强大遗传模型。我们将首先研究已知的相对贡献

DESCRIPTION (provided by applicant): Axon guidance and synaptogenesis represent distinct biological processes in the development of a neuron, yet they are mediated by an overlapping set of extrinsic cues, including netrin, wnt, and semaphorin. In axon guidance, these cues modulate the formation of actin filaments (F- actin) into the filopodial extensions of the growth cone, whereas in synaptogenesis, they direct F-actin assembly at nascent presynaptic regions to scaffold the recruitment of the presynaptic assembly program. To ascertain how the same extrinsic cues instruct dissimilar actin dynamics when specifying axon guidance versus synaptogenesis, we will examine the mechanisms of actin regulation during these two processes in Caenorhabditis elegans. As C. elegans is translucent, its stereotyped axon morphology and synapse patterning are easily observed using cell- and synapse-specific fluorescent markers. Furthermore, the ease of conducting forward genetic screens, combined with the wealth of available characterized mutants, makes C. elegans a powerful genetic model for the study of neuronal development. We will first investigate the relative contribution of known actin regulators to axon guidance and synaptogenesis in a specific neuron. We hypothesize that subsets of actin regulators have an exclusive role in either axon guidance or synaptogenesis, and that the differential regulation and function of these actin regulators underlies the distinct actin dynamics involved in these two processes. In parallel, we will use a forward genetic approach to identify novel genes which link synapse-patterning cues to presynaptic F-actin assembly. Finally, by examining genetic interactions between actin regulators and the multiple extrinsic cues which mediate axon guidance and synaptogenesis in a single cell, we will uncover how these cues converge to modulate actin dynamics. Aberrant actin regulation in neurons has been linked to a number of neurological disorders, including Parkinson's disease and autism. A more complete understanding of the mechanisms of actin regulation in neurons is an important step in designing effective therapies for these conditions.