Regulation of cellular interactions and synapse development in the CNS.

大脑是由相互连接的细胞组成的网络。它们的功能依赖于连接的选择性形成，因此它们的行为类似于适当配置的信息处理机器。形成联系的过程虽然至关重要，但人们并不清楚，尤其是我们对生活网络中发生的事情一无所知，因为它们形成、建立联系并开始发挥作用。随着神经系统的发育，神经细胞终末也会生长。这些终端的增长与它们上的连接的形成密切相关。因此，在正常发育过程中，神经末梢的生长受到严格的调控，以确保出现正常的功能。相反，调节神经末梢生长或神经末梢之间连接形成的基因突变与智力低下、认知障碍和神经退化有关。除了神经细胞，所谓的神经胶质细胞也对神经系统的组成有贡献。近年来，神经胶质细胞因其在调节神经细胞之间形成的连接的形成和功能方面的作用而受到重视。然而，我们对神经胶质细胞如何与神经细胞相互作用从而调节神经末梢生长和连接的了解尤其参差不齐。其中一个原因是细胞间的相互作用是非常动态的，在发育中的神经系统中对相互作用的细胞进行差异化标记和成像一直是一项极具挑战性的工作。我们在果蝇胚胎中有一个简单的模型网络。重要的是，大多数发育过程在进化过程中是保守的。正是出于这个原因，也因为人们可以相对容易地进行苍蝇遗传学，果蝇在推动我们对神经系统发育的理解方面发挥了重要作用。我们开发了新的遗传学、显微镜和电生理学方法，使我们能够研究和操纵这个系统中的特定细胞。利用遗传学，我们可以(用荧光染料)不同地标记伴侣神经和神经胶质细胞。使用我们的显微镜装置，我们可以想象这些细胞在它们的终末生长、彼此形成连接和成熟时是如何相互作用的。我们将准确地确定连接形式发生了什么--我们可以在整个发展阶段从形态和功能(作为一个信号连接)来研究它。通过最近的基因筛查，我们发现了一种名为间变性淋巴瘤激酶(ALK)的基因，它是神经末梢生长的重要调节因子。改变该基因活性的突变已被发现会导致人类癌症，这方面已经进行了研究。然而，ALK的其他功能，即在神经系统发育过程中的功能，还不太清楚。我们的初步工作有力地表明，ALK对于调节神经细胞和神经胶质细胞之间的通讯是重要的，因此它可能调节神经末梢的生长。我们将应用我们的基因和成像方法来检验这一假说。在确定了ALK功能改变对神经系统发育造成的后果后，我们将调查潜在的机制，以了解这些变化是如何发生的。这项工作的结果将帮助我们理解形成正常运作的神经系统所需的机制和分子。

Brains are networks of interconnected cells. Their functions depend on the selective formation of connections, so that they behave as appropriately configured information processing machines. The process of forming connections, though vital, is not well understood, and we are particularly ignorant of what happens in living networks as they form, make connections and begin to function. As nervous systems develop, nerve cell terminals grow. The growth of these terminals is intimately linked to the formation of connections on them. During normal development, nerve terminal growth is therefore tightly regulated, so as to ensure that normal function can emerge. Conversely, mutations in genes that regulate nerve terminal growth or the formation of connections between them have been linked to mental retardation, cognitive disorders and neurodegeneration. In addition to nerve cells, so-called glia cells also contribute to the make up of the nervous system. Glia cells have in recent years become appreciated for their role in regulating the formation and function of connections that nerve cells form between each other. However, our understanding of how glia cells interact with nerve cells so as to regulate nerve terminal growth and connectivity is particularly patchy. One reason for this is that cell-cell interactions are very dynamic and it has been exceedingly challenging to differentially label and image interacting cells in a developing nervous system. We have a simple model network in the fruitfly fly embryo. Importantly, most developmental processes have been conserved during evolution. It is for this reason and because one can do fly genetics with relative ease, that the fruitfly has been instrumental in driving forward our understanding of nervous system development. We have developed new genetic, microscopy and electrophysiological methods that allow us to study and manipulate particular cells in this system. Using genetics, we can differentially label partner nerve and glia cells (with fluorescent dyes). Using our microscope setup we can image how these cells interact as their terminals grow, form connections with one another and mature. We will determine precisely what happens as connections form - we can study it both morphologically and functionally (as a signaling junction) throughout the period of its development. Through a recent genetic screen we have identified a gene called Anaplastic lymphoma kinase (Alk) as an important regulator of nerve terminal growth. Mutations that alter the activity of this gene have been found to cause cancers in humans and this aspect has been studied. However, other functions of Alk, namely during nervous system development are less well understood. Our preliminary work strongly suggests that Alk is important for regulating the communication between nerve cells and glia and that it may thus regulate nerve terminal growth. We will apply our genetic and imaging methods to test this hypothesis. Having established the consequences of what happens to nervous system development when Alk function is altered, we will investigate underlying mechanisms to understand how these changes occur. The results from this work will help us understand the mechanisms and molecules that are required to form a functioning nervous system.