The function of alpha-spectrin in the Drosophila nervous system

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Within the developing nervous system cell polarity is mostly evident in neuronal cells which form dendrites and axons with strictly separate membrane domains. We are interested in the role of cell polarity for the developing glial cells. In the Drosophila CNS the midline glial cells show a pronounced initial apico-basal polarity. During later developmental stages, the glial cells form basal cell processes that migrate towards commissural axons and concomitantly retract their apical cell processes. This polar cell organization is disturbed in klötzchen mutants that we have previously identified in a phenotypic screen. Klötzchen fails to complement alpha-spectrin and the mutant klötzchen phenotype can be rescued by expression of aspectrin using the ubiquitin promoter. Furthermore, klötzchen mutant cell clones lack alpha-spectrin expression. However, the alpha-spectrin null phenotype differs from the phenotype of the 8 independent klötzchen alleles that we have identified. In addition, the Drosophila alpha-spectrin gene is unusual as it encodes a second gene within its first intron that shares the first noncoding exon with the alpha-spectrin transcript. In the next two years we propose to molecularly identify the klötzchen mutation in either the alpha-spectrin gene or the intron-based gene. We want to address the question how the loss of alpha-spectrin leads to a disruption of the polar glial cells phenotype. Using other mutations affecting cell polarity we will determine whether glial cell polarity is required for later differentiation / function. In addition to further detailed phenotypic analyses, we will perform structure function studies of a-spectrin as well as we will perform genetic screens aimed to identify genes interacting with klötzchen. Our experiments will contribute to the understanding how alpha-spectrin regulates cell polarity and how this polarity is required for subsequent glial cell function.