Genes Essential To Motor Axon Guidance in Drosophila

描述（由申请人提供）：在神经系统发育和再生过程中，需要细胞内机制控制生长锥导航到适当的靶细胞，以建立功能性神经连接网络。我们对多种引导受体下游的细胞骨架信号机制的长期兴趣使我们发现了一系列保守的微管相关蛋白，它们似乎介导不同类型的引导行为。对效应蛋白CLASP的分析确定了一条从排斥因子Slit及其Roundabout受体到Abelson酪氨酸激酶再到CLASP的途径，作为阻碍微管和前沿进展的手段。Abl如何协调微丝和微管动力学，并控制CLASP或其相关伙伴的活性尚不清楚。初步数据表明，与CLASP直接或间接相关的几种蛋白质是精确中线排斥所必需的，而其他微管效应蛋白似乎在早期轴突引导决策中发挥着不同的作用。我们将结合遗传学、细胞生物学和生物化学来确定每种蛋白质在轴突引导中的功能，并剖析调节关键效应物活动的信号机制。

DESCRIPTION (provided by applicant): The intracellular mechanisms that control growth cone navigation to appropriate target cells are required to build networks of functional neural connections during nervous system development and regeneration. Our long-standing interest in the cytoskeletal signaling machinery downstream of multiple guidance receptors has led us to a series of conserved microtubule-associated proteins that appear to mediate different types of guidance behavior. Analysis of the effector protein CLASP has defined a pathway from the repellent factor Slit and its Roundabout receptors, to the Abelson tyrosine kinase, to CLASP, as a means of impeding microtubule and leading edge advance. How Abl acts to coordinate microfilament and microtubule dynamics, and control the activity of CLASP or its associated partners is unknown. Preliminary data indicates that several proteins directly or indirectly linked to CLASP are required for accurate midline repulsion, whereas other microtubule effector proteins appear to play distinct roles in early axon guidance decisions. We will use a combination of genetics, cell biology and biochemistry to determine each protein's function in axon guidance and to dissect the signaling mechanisms that regulate the key effector activities.