Cis mutagenesis in vivo reveals extensive noncanonical functions of Dscam1 isoforms in neuronal wiring

Drosophila Dscam1 encodes ten thousand of cell recognition molecules via alternative splicing, which is required for nervous function. However, the underlying mechanism has not fully understood. Here we revealed extensive noncanonical functions of Dscam1 isoform diversity in neuronal wiring. We generated a series of allelic cis mutations in Dscam1, encoding normal number of isoforms albeit with altered isoform composition. Despite normal dendritic self-avoidance and self/non-self discrimination in da neurons, which is consistent with canonical self-avoidance model, these mutants exhibited strikingly distinct spectra of phenotypic defects in three classes of neurons: up to [~]60% defects in mushroom bodies, a significantly increased branching and growth in da neurons, and mild axonal branching defects in mechanosensory neurons. These data suggest that proper Dscam1 isoform composition is required for axon and dendrite growth in diverse neurons. This unprecedented splicing-tuned regulation unlocks new insights into the molecular mechanisms that Dscam1 isoform diversity is engaged in.