The experiments outlined in this proposal seek to isolate and characterize the gene and gene product, responsible for the mutation of the wobbler (wr) mouse, a model of spinal muscular atrophy. A novel approach will be used, applying subtractive and differential hybridization, to isolate ventral spinal cord-specific cDNAs. These probes will then be used to isolate candidate wr cDNA clones by screening a spinal cord cDNA library of normal mice, and a cDNA library made from the ventral cord of the wr mouse. Northern blots of control and wobbler mRNA of developing and adult mice will be hybridized with the candidate wr cDNAs to determine differences in size and time of expression. This will help further narrow down the potential wr clones. Southern blots of control, heterozygote, and wobbler DNA will also be hybridized to the potential wr cDNAs to determine whether them are structural differences between normal and affected animals at the DNA level. The nucleotide sequence of the putative wr cDNA will be determined and antino acid sequence will be deduced. If the protein is already known, antibodies and probes will be used to further characterize its role in the wr phenotype. If it is an unknown protein, synthetic peptides will be made and antibodies will be raised to isolate and characterize the wr protein. Chromosomal analysis will also be performed using mapping techniques, and genomic libraries will be screened for the putative gene. This work will lead to an improved understanding of anterior horn cell physiology and pathology, and hopefully give new insight into human motor neuron disease.
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