Deterministic splicing ofDscam2is regulated by Muscleblind

Summary Alternative splicing of genes increases the number of distinct proteins in a cell. In the brain it is highly prevalent, presumably because proteome diversity is crucial for establishing the complex circuitry between trillions of neurons. To provide individual cells with different repertoires of protein isoforms, however, this process must be regulated. Previously, we found that the mutually exclusive alternative splicing of a cell surface protein, Dscam2 produces two isoforms (exon 10A and 10B) with unique binding properties. This splicing event is tightly regulated and crucial for maintaining axon terminal size, dendritic morphology and synaptic numbers. Here, we show that Drosophila Muscleblind (Mbl), a conserved splicing factor implicated in myotonic dystrophy, controls Dscam2 alternative splicing. Removing mbl from cells that normally express isoform B induces the expression of isoform A and eliminates the expression of B, demonstrating that Mbl represses one alternative exon and selects the other. Mbl mutants exhibit phenotypes that are also observed in flies engineered to express a single isoform. Consistent with these observations, mbl expression is cell-type-specific and correlates with the expression of isoform B. Our study demonstrates how the regulated expression of a splicing factor is sufficient to provide neurons with unique protein isoforms crucial for development.