The Genetic Specification of Neuron-target Interactions: The Role of LOLA

摘要 IBN-9723376 GINIGER 在大脑和神经系统的发育过程中，神经细胞通常必须将其轴突延伸很长一段距离才能找到特定的目标。 例如，在肢体的发育过程中，每一块肌肉都必须受到一组特定的运动神经元的支配，才能正常发挥功能。 在其生长过程中，神经元轴突的尖端会做出一系列决定，决定转向何处、向何处转向，以及何时停止并形成突触连接。 我们知道，神经元在每个决策点都会对复杂的外部信号做出反应。 然而，我们不知道是什么机制协调了所有这些信号的表达，以及是什么确保神经细胞具有适当的机制来识别特定时间的适当信号。 先前的工作已经在果蝇中确定了一个似乎协调特定神经元指导决定的单一基因。 在缺乏这种基因（称为lola）的情况下，特定的神经无法识别它们的目标，而在产生过多lola的动物中，这些神经似乎与它们的目标相互作用过强。 LOLA蛋白的结构表明，它通过开启和关闭其他基因的表达来发挥作用，这些基因的产物可能直接负责神经元靶点识别。 Giniger博士实验的目的是了解lola的哪些特性为神经-靶点相互作用提供了特异性。 特别是，这些实验将测试这样一种想法，即神经与目标的匹配是因为一种形式的lola在目标细胞中产生并使它们产生信号分子，而第二种形式的lola在神经细胞中产生，使它们产生信号接收器。 这些实验也将检验lola能够协调几种不同的生长决定的观点，因为在每种情况下，它都与不同的蛋白质伙伴一起工作。 大脑是生物学中最复杂的结构，我们对它的组织是如何建立的知之甚少。 这些实验将测试基因决定大脑结构的机制的简单模型。 很可能，这里在苍蝇身上测试的原理将同样适用于所有动物的大脑发育。

ABSTRACT IBN-9723376 GINIGER During the development of the brain and nervous system, a nerve cell often must extend its axon over a long distance to find a particular target. In the development of a limb, for example, each muscle must become innervated by a specific set of motor neuron for the limb to function properly. During the course of its growth, the tip of a neuron's axon makes a whole series of decisions about where and which way to turn, and about when to stop and form a synaptic connection. We know that the neuron responds to a complex constellation of external signals at each of these decision points. We do not understand, however, what mechanism coordinates the expression of all of these signals, and what ensures that the nerve cell has the proper machinery to recognize the appropriate set of signals at a particular time. Previous work has identified a single gene in the fruitfly Drosophila that seems to coordinate particular neuron guidance decisions. In the absence of this gene (called lola), specific nerves fail to recognize their targets, whereas in animals that make too much lola, these same nerves seem to interact too strongly with their targets. The structure of the LOLA protein suggests that it works by turning on and off the expression of other genes, perhaps the genes whose products are directly responsible for neuron-target recognition. The goal of Dr. Giniger's experiments is to understand what properties of lola provide specificity to nerve-target interactions. In particular, these experiments will test the idea that the matching of nerve to target occurs because one form of lola is made in target cells and causes them to produce signal molecules, while a second form of lola is made in nerve cells that causes them to produce signal-receivers. These experiments will also test the idea that lola can coordinate several different growth decisions because, in each case, it works together with a different partner protein. The brain is the most complex stru cture in biology, and we understand little about how its organization is established. These experiments will test a simple model for the mechanism by which genes determine brain structure. It is likely that the principles tested here in the fly will be equally applicable to the development of the brain in all animals.