MOLECULAR GENETICS OF NEURAL SPECFICITY

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The long term goal of the proposed research is to understand the molecular basis of neural specificity. Particular patterns of connectivity in different regions of the brain are correlated with specific functional tasks. Little is known, however, of how these networks are established. How do neurons choose appropriate synaptic partners? We have isolated a gene, unc-4 which controls the pattern of synaptic input to specific motor neurons in the nematode, C. elegans. In mutants lacking a functional unc-4 gene, input from interneurons which normally synapse with VA motor neurons is replaced with input from presynaptic partners appropriate to VB motor neurons. We have shown that unc-4 encodes a transcription factor that is expressed in the VA motor neurons but not in the VB's Thus, unc-4 may control the expression of another gene product that distinguishes the VA neuroblast from its VB sister cell. The question then becomes, What is the gene that unc-4 regulates? We have identified a candidate, the unc-37 gene. Mutations that disable unc-37 gene function cause an Unc-4-like phenotype (can't back up) and suppressor mutations that map to the unc-37 locus restore normal movement to an unc-4 mutant. Perhaps unc-37 encodes a cell surface protein that is expressed in VA motor neurons to mediate input from one set of presynaptic partners and not from another. The unc-37 gene will be isolated by complementation. The DNA sequence of the unc-37 gene will be determined to deduce the primary structure of the corresponding protein product. Fragments of the unc-37 protein will be produced in bacteria and used to prepare specific antisera. Immunological techniques will be used to identify the pattern of unc-37 expression. Mosaic analysis will be performed to identify the cells in which unc-37 gene will be reconstructed by serial section electron microscopy to define the neural defect. With this biochemical and morphological data, it should be possible to formulate a model to explain the molecular mechanism of unc-37 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.