For a nervous system to be wired properly, the axons have to be guided toward the correct targets and the dendrites need to have the correct branching pattern and structural specialization. At present, much less is known about the molecular mechanisms that control dendrite development as compared to those controlling axon guidance. A few years ago, our lab initiated a very fruitful genetic dissection of dendrite development using Drosophila Multiple Dendritic neurons as a model system. This ongoing genetic screen has begun to yield important insights about the molecular basis of dendrite development in Drosophila. Given the striking conservation of many molecular mechanisms that control various developmental processes including axon guidance, it is highly likely that the molecular mechanisms controlling dendrite development is conserved between fly and mammals. Indeed, we already have considerable success in our initial efforts to extend our findings from Drosophila to mammalian CNS. We discovered that mPar3/mPar6 have evolutionarily conserved role in controlling neuronal polarity. Further, we discovered a novel Arborless receptor family that has a specific role in controlling dendritic arborization in both fly and mammals. We propose to carry out in depth phenotypic and molecular studies of the """"""""Key genes"""""""" already found and to scale up our effort to systematically identify mammalian functional homologues of the Drosophila genes that are key regulators of various aspects of dendrite development. These Key genes should lead to the identification of evolutionarily conserved """"""""Core programs"""""""" that control dendrite development in all animals. Our approach is likely to be fruitful in unraveling the molecular mechanisms that control dendrite development in mammalian CNS. The Core programs identified from this work will contribute to the understanding and eventual treatment of human neurological diseases many of which have pathology in dendrites.
