Molecular genetics of the development of the brain center for learning and memory and its regulatory gene network in Drosophila

果蝇为研究大脑发育的遗传程序提供了一个极好的模型系统。在众多的神经元结构中，蘑菇体被认为是果蝇的联想学习和记忆中心。虽然大多数关于果蝇大脑的研究都集中在成年大脑的功能和解剖结构上，但关于发育和调控基因网络的知识仍然有限。通过分子神经解剖学技术，我们已经确定了果蝇Pax 6同源基因eyeless（ey）和twin of eyeless（toy）是蘑菇体发育的关键调控基因。我们还发现，另一种调节剂，腊肠犬（dachshund，Dachshund），在MB神经元的轴突分化中具有重要作用。虽然这些基因最初是在眼睛发育中发现的，但大脑发育中涉及不同的调控相互作用; eye，toy和proximal的表达都是独立调控的。通过增强子捕获技术筛选新基因，已经鉴定出许多在发育中的蘑菇体中表达的核调控基因。此外，在分子分析的过程中的监管级联，我们发现同心的幼虫MB的神经层，并表明，细胞粘附分子，FAS II，是至关重要的MB层的完整性。突变体和RNAi研究表明ey和toy在脑发育中具有不同的功能，其中ey是MB神经元轴突分化所需的，toy是广泛脑模式所需的。对ey基因调控区的分子解剖已经确定了上游和内含子增强子，它们协同驱动大脑中的基因。这些结果为理解蘑菇体的发育机制提供了重要信息，并提出了复杂大脑嗅觉学习中心早期发育的保守遗传程序。

Drosophila provides an excellent model system for the dissection of the genetic program of brain development. Among various neuropil structures, mushroom bodies (MBs) are considered as the centers for associative learning and memory in flies. Whereas most studies on the fly brain have focused on the functions and anatomy of the adult brain, knowledge about the development and the regulatory gene network is still limited. By molecular neuroanatomical techniques, we have identified eyeless (ey) and twin of eyeless (toy) the two Drosophila Pax6 homologs, as the key regulatory genes in the development of the mushroom bodies. We have also found that another regulator, dachshund (dac), has an important role in axonal differentiation of the MB neurons. Whereas these genes are originally identified in eye development, different regulatory interactions are involved in brain development ; expression of ey, toy and dac are all independently regulated. Screening for novel genes by the enhancer-trap technique has identified many nuclear regulatory genes expressed in the developing mushroom bodies. Furthermore, in the course of molecular analysis of the regulatory cascade, we have revealed concentric neural layers of the larval MBs and shown that a cell adhesion molecule, FAS II, is crucial for the integrity of the MB layers. Mutant and RNAi studies have shown that ey and toy have distinct functions in brain development, in which ey is required for axonal differentiation of the MB neurons and toy is required for broad brain patterning. Molecular dissection of the regulatory regions of the ey gene has identified upstream and intronic enhancers that cooperatively drive the gene in the brain. These results provide important information for understanding the developmental mechanisms of the mushroom bodies and suggest conserved genetic programs of the early development of the olfactory learning centers of complex brains.