Mechanisms of axon guidance during development

在发育过程中，神经连接的正确模式是如何建立的？这种模式在成人神经系统中是如何维持的呢？这些都是Axon Guidance and Neural Connectivity Unit试图回答的问题。 为了理解神经连接建立的机制，我们关注的是神经连接过程中所谓的“基本事件”，即单个细胞表面受体告诉发育中的神经元在哪里生长以找到其突触伙伴的机制。我们研究了一种特殊的细胞表面受体，叫做Notch。Notch之所以引人注目，是因为除了指导神经生长外，它还控制树突的分支、神经元（和许多其他类型的细胞）的身份、神经元的出生数量以及细胞的存活或死亡。因此，它控制着动物发育的许多方面，并导致各种人类疾病，包括某些类型的癌症和中风。因此，我们对轴突中Notch的了解对生物学和健康的影响远远超出了我们正在研究的特定过程。以前对Notch的研究集中在这种普遍存在的受体的单一信号传导机制上。然而，我们发现，这只是故事的一半。胚胎中约5%的Notch蛋白是酪氨酸磷酸化的，并且该分子群体特异性地与另一组下游效应物Abl癌基因及其相关辅助因子相关联，以直接控制细胞-细胞接触、细胞形状和细胞迁移。此外，我们已经证明，这种替代Notch信号通路作用于质膜（与靶向细胞核中事件的标准信号通路相反），并且它通过一种称为Rac的蛋白质起作用，Rac是肌动蛋白细胞骨架和细胞粘附复合物的直接调节剂。在生长的神经中，Notch/Abl/Rac机制的活性被揭示为神经生长的方向和程度的调节。目前的实验旨在继续阐明这种替代信号通路的分子机制，并确定除了生长轴突外，它还可能在生物学和疾病中起作用。我们特别感兴趣的证据表明，我们发现的替代Notch信号通路可能是控制神经和胚胎干细胞存活的核心，并且它是Notch激活导致癌症的机制的关键，包括髓母细胞瘤，白血病，横纹肌肉瘤和乳腺癌。

How is the proper pattern of neural connections established during development? And how is that pattern maintained in the adult nervous system? These are the questions that the Axon Guidance and Neural Connectivity Unit seeks to answer. To understand the mechanisms underlying the establishment of neural connections, we focus on what might be termed the "elementary event" in the process of neural wiring, the mechanism by which a single cell-surface receptor tells a developing neuron where to grow in order to find its synaptic partners. We study a particular cell surface receptor called Notch. Notch is notable because, in addition to directing nerve growth, it also controls the branching of dendrites, the identities of neurons (and many other types of cells), how many neurons are born and whether cells live or die. As such, it controls many aspects of animal development and is responsible for a wide array of human diseases, including some kinds of cancer and stroke. What we learn about Notch in axons, therefore, has implications for biology and health far beyond the particular process we are examining. Previous studies of Notch have focused on a single signaling mechanism for this ubiquitous receptor. We have found, however, that this is only half of the story. About 5% of the Notch protein in the embryo is tyrosine phosphorylated, and this population of molecules associates specifically with an alternate group of downstream effectors, the Abl oncogene and its associated accessory factors, to directly control cell-cell contacts, cell shape and cell migration. We have shown, moreover, that this alternate Notch signaling pathway acts at the plasma membrane (as opposed to the standard signaling pathway, which targets events in the cell nucleus), and that it acts via a protein called Rac that is a direct regulator of the actin cytoskeleton and of cell-adhesion complexes. In growing nerves, the activity of the Notch/Abl/Rac machinery is revealed as regulation of the direction and extent of nerve growth. Current experiments are directed at continuing to elucidate the molecular mechanism of this alternate signaling pathway, and to determine where besides growing axons it may act in biology and disease. We are particularly interested by evidence that the alternate Notch signaling pathway we have discovered may be central to controlling the survival of neural and embryonic stem cells, and that it is key to the mechanism by which activation of Notch can cause cancers, including medulloblastoma, leukemia, rhabdomyosarcoma and breast cancer.