MOLECULAR GENETICS OF NEURAL SPECIFICITY

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The long term goal of the proposed research is to understand the molecular basis of neural specificity. The human brain is composed of about 100 billion neurons each of which forms multiple synapes to establish an elaborate yet specific network of communicating cells. How does each of these neurons recognize the appropriate partners from among the myriad cells types that contribute to the system? The objective of this proposal is to employ a molecular genetic approach as a first step toward answering this question. In the nematode, Caenorhabditis elegans, the complete anatomy of the nervous system has been determined. As a result of this detailed information, mutants exhibiting behavioral defects have been correlated with specific alterations in neuronal morphology. Mutations in the unc-4 gene movement and cause specific changes in the organization of the ventral nerve cord. In unc-4 mutants, a characteristic network of synaptic inputs to the VA class of motor neurons is replaced with an innervation pattern normally reserved for VB motor neurons. Other types of neurons are not affected by the unc-4 mutation. Thus, the unc-4 gene is necessary for the establishment of a particular pattern of synapse formation. The unc-4 gene will be isolated from C. elegans by a transposon tagging technique. The DNA sequence of the unc-4 gene will be determined in order to deduce the primary structure of the corresponding protein product. Fragments of the unc-4 protein will be produced in bacteria and used to prepare specific antibodies. Immunological techniques will be employed to identify the endogenous unc-4 protein and the cells in which it is expressed. With this biochemical information, it should be possible to formulate a model to explain the molecular mechanism of unc-4 action. Furthermore, it is expected that the nucleic acid and immunological probes that will be derived from this work can be employed to identify homologous genes and proteins with similar functions in other more complex nervous systems.