GROWTH CONE TUNING INDUCED BY DIFFUSIBLE MOLECULES

在发育过程中形成特定的神经连接需要 引导伸长轴突的生长尖端，即生长锥， 正确的靶细胞。 生长锥对各种有吸引力的 或排斥性引导分子存在于环境中 通过转向或转向远离而扩散或表面结合， 分别 生长锥通过细胞过程来检测 不同的扩散线索和改变其延伸方向仍然存在 有待阐明。 在这项研究中，我们的目标是了解生长锥是如何 检测不同分子的细胞外梯度， 细胞内的方向信息，并做出适当的改变， 在其延伸方向上。 我们的工作假设如下： 不同细胞特异性受体的激活梯度 由不同的第二信使和激酶介导的可扩散线索， 所有这些都导致了一组共同的 生长锥中的蛋白质 活化的蛋白质反过来调节 生长锥的细胞骨架动力学不对称， 生长锥运动的不对称调节，导致 反应 使用从非洲爪蟾胚胎制备的神经元培养物，我们 将检验我们的假设具体而言，我们将确定：（1） 第二信使Ca和cAMP在编码 方向信息，以指导生长锥延伸;（2） 与生长锥相关的不对称细胞事件序列 运动性是生长锥转动所必需的 不同的引诱剂和驱避剂诱导;（3）不对称 细胞骨架和膜事件与转动的 生长锥 这些研究背后的计划是共同的 不同生长因子诱导生长锥转向的机制 可扩散分子 细胞和分子机制的阐明 参与生长锥的指导是至关重要的， 正常和病理状态下神经系统的发育 条件 此外，这项研究的结果将提供 重要的见解之间的各种细胞外的缺失环节 线索和调节神经生长。

Formation of specific nerve connections during development requires the guidance of the growing tip of elongating axons, the growth cone, to its correct target cells. Growth cones respond to a variety of attractive or repulsive guidance molecules present in the environment that are either diffusible or surface-bound by turning towards or away, respectively. The cellular processes by which a growth cone detects different diffusible cues and alters its direction of extension remain to be elucidated. In this study, we aim to understand how a growth cone detects the extracellular gradients of different molecules, relays the directional information intracellularly, and makes appropriate changes in its direction of extension. Our working hypothesis, is as follows: gradients of activation of cell-specific receptors for different diffusible cues, mediated by different second messengers and kinases, all lead to a cytoplasmic gradient in the activation of a common set of proteins in the growth cone. The activated proteins in turn regulate cytoskeletal dynamics at the growth cone asymmetrically to result in an asymmetric modulation of growth cone motility, leading to the turning response. Using neuronal cultures prepared from Xenopus embryos, we will test our hypothesis. Specifically we will determine: (1) the precise role of second messengers Ca and cAMP in encoding the directional information to direct the growth cone extension; (2) the sequence of asymmetric cellular events associated with growth cone motility that are common and essential for turning of growth cones induced by different attractants and repellents; (3) the asymmetric cytoskeletal and membranous events associated with the turning of the growth cone. The scheme underlying these studies is the common mechanisms underlying the turning of growth cones induced by different diffusible molecules. Elucidation of cellular and molecular mechanisms involved in growth cone guidance is critical for our understanding of the development of the nervous systems in normal and pathological conditions. Furthermore, the results from this study will provide important insights on the missing link between various extracellular cues and the regulated nerve growth.