How Do Cadherins Control Photoreceptor Connectivity?

描述(申请人提供)：视网膜中的神经元与它们的突触目标建立了非常精确的联系。事实上，这种精确度是大脑许多部分神经元连接的标志。这些突触模式定义了神经系统的接线图，并在一定程度上决定了大脑的计算方式。这些连接中的许多都是在没有感觉输入的情况下通过基因编程形成的。然而，基因组如何编码关于这些连接模式的信息并应用这些信息来指定每个神经元的靶标的分子机制还知之甚少。果蝇的视觉系统提供了一个独特的机会，可以利用遗传技术来确定这种机制如何控制神经元靶标的选择。例如，光感受器细胞与一组空间不变的突触后伙伴建立突触连接，并且可以在没有视觉输入的情况下做到这一点。如此精确的一组联系怎么可能是遗传上的硬连线呢？拟议的实验在一组特殊的神经细胞黏附分子--钙粘附素的背景下检验了这些机制。这些蛋白质被认为在控制突触形成方面发挥关键作用。经典钙粘附素如何影响突触伴侣的选择？(目的1)经典钙粘附素在神经元中的功能是如何调节的？(目标2)其他钙粘附素是否也在神经元靶标选择中发挥作用？(目的3)钙粘附素功能的遗传紊乱会导致遗传性的视网膜色素变性、黄斑变性和大脑发育缺陷。然而，大脑中钙粘附素功能的分子机制几乎完全未知。在一个简单的模型系统中了解这些功能可能会提出新的治疗策略。

DESCRIPTION (provided by applicant): Neurons in the retina make remarkably precise connections with their synaptic targets. Indeed, such precision is a hallmark of neuronal connectivity in many parts of the brain. These synaptic patterns define the wiring diagram of the nervous system and determine, in part, how the brain computes. Many of these connections are genetically programmed to form in the absence of sensory input. However, the molecular mechanisms that underlie how the genome encodes information about these patterns of connections and applies this information to specify the targets of each individual neuron are poorly understood. The visual system of Drosophila presents a unique opportunity to use genetic techniques to determine how such mechanisms can control neuronal target selection. Photoreceptor cells, for example, make synaptic connections with a spatially invariant group of post-synaptic partners, and can do so in the absence of visual input. How can such a precise set of connections be genetically hard-wired? The proposed experiments examine these mechanisms in the context of one particular group of neuronal cell adhesion molecules, the cadherins. These proteins are thought to play critical roles in controlling synapse formation. How do classical cadherins influence synaptic partner choice? (Aim 1) How are the functions of classical cadherins regulated in neurons? (Aim 2) Do other cadherins also play a role in neuronal target selection? (Aim 3) Genetic disruptions in cadherin function cause inherited forms of retinitis pigmentosa, macular degeneration and defects in brain development. However, the molecular mechanisms that underlie cadherin functions in the brain are almost entirely unknown. Understanding these functions in a facile model system may suggest novel therapeutic strategies.