Deterministic splicing of <i>Dscam2</i> is regulated by Muscleblind.

Abstract

Alternative splicing increases the proteome diversity 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 <i>Drosophila Dscam2</i> produces two isoforms (A and B) with unique binding properties. This splicing event is cell type specific, and the transmembrane proteins that it generates are crucial for the development of axons, dendrites, and synapses. Here, we show that Muscleblind (Mbl) controls <i>Dscam2</i> alternative splicing. Mbl represses isoform A and promotes the selection of isoform B. <i>Mbl</i> mutants exhibit phenotypes also observed in flies engineered to express a single <i>Dscam2</i> isoform. Consistent with this, <i>mbl</i> expression is cell type specific and correlates with the splicing 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.