Comprehensive Characterization of the Complex lola Locus Reveals a Novel Role in the Octopaminergic Pathway via Tyramine Beta-Hydroxylase Regulation

Abstract

Summary: Longitudinals lacking (lola) is one of the most complex genes in Drosophila melanogaster, encoding up to 20 protein isoforms that include key transcription factors involved in axonal pathfinding and neural reprogramming. Most previous studies have employed loss-of-function alleles that disrupt lola common exons, making it difficult to delineate isoform-specific functions. To overcome this issue, we have generated isoform-specific mutants for all isoforms using CRISPR/Cas9. This enabled us to study specific isoforms with respect to previously characterized roles for Lola and to demonstrate a specific function for one variant in axon guidance via activation of the microtubule-associated factor Futsch. Importantly, we also reveal a role for a second variant in preventing neurodegeneration via the positive regulation of a key enzyme of the octopaminergic pathway. Thus, our comprehensive study expands the functional repertoire of Lola functions, and it adds insights into the regulatory control of neurotransmitter expression in vivo. : lola is among the most complex loci in Drosophila, playing important roles in axonal pathfinding and neural reprogramming. Using a targeted CRISPR/Cas9 mutational screening of every lola isoform, Dinges et al. revisit Lola functions, and they identify a critical role for one specific variant in the octopaminergic pathway. Keywords: Lola, octopaminergic neurons, splicing, axon guidance, isoforms, CRISPR/Cas9, Tyramine beta-hydroxylase, Futsch