The PSI–U1 snRNP interaction regulates male mating behavior in Drosophila

Significance How gene regulation orchestrates brain activities that lead to cognition and behavior remains a challenging question in biology. Alternative pre-mRNA splicing (AS) is a crucial mechanism that is extensively used in the brain to generate diverse and functionally distinct protein products from a limited number of eukaryotic genes, and can thereby switch neuron functions and rewire neural circuits for different behaviors. Here, we elucidate the function of an essential AS regulatory protein, P-element somatic inhibitor (PSI), in coordinating male courtship behavior in the fruit fly Drosophila melanogaster. We show that PSI fine-tunes the AS patterns of a dynamic network of neural gene transcripts and exerts precise control of male mating behavior. Our results provide important information into mechanisms for behavior control in animals. Alternative pre-mRNA splicing (AS) is a critical regulatory mechanism that operates extensively in the nervous system to produce diverse protein isoforms. Fruitless AS isoforms have been shown to influence male courtship behavior, but the underlying mechanisms are unknown. Using genome-wide approaches and quantitative behavioral assays, we show that the P-element somatic inhibitor (PSI) and its interaction with the U1 small nuclear ribonucleoprotein complex (snRNP) control male courtship behavior. PSI mutants lacking the U1 snRNP-interacting domain (PSIΔAB mutant) exhibit extended but futile mating attempts. The PSIΔAB mutant results in significant changes in the AS patterns of ∼1,200 genes in the Drosophila brain, many of which have been implicated in the regulation of male courtship behavior. PSI directly regulates the AS of at least one-third of these transcripts, suggesting that PSI–U1 snRNP interactions coordinate the behavioral network underlying courtship behavior. Importantly, one of these direct targets is fruitless, the master regulator of courtship. Thus, PSI imposes a specific mode of regulatory control within the neuronal circuit controlling courtship, even though it is broadly expressed in the fly nervous system. This study reinforces the importance of AS in the control of gene activity in neurons and integrated neuronal circuits, and provides a surprising link between a pleiotropic pre-mRNA splicing pathway and the precise control of successful male mating behavior.

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