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

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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.