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In Drosophila melanogaster, male-specific behaviours, such as courtship, are driven by the expression of male-specific isoforms of the transcription factors encoded by fruitless (fru). However, the mechanisms by which male-specific FRU mediates these effects are unknown. Yamamoto and colleagues show that FRU interacts with two antagonistic chromatin modifiers to regulate the development of a sexually dimorphic neural circuitry.

To identify proteins that may interact with FRU to execute its masculinizing effects, the authors conducted a genetic suppressor screen. A loss-of-function mutation in bonus (bon), which encodes the transcriptional cofactor BON, suppressed the phenotypic effects of fru overexpression in flies. Furthermore, a bon loss-of-function mutation exacerbated the reduction in courtship behaviour observed in male flies carrying a loss-of function mutation in fru, confirming the importance of BON for the sex-specific effects of fru expression.

Mammalian homologues of BON silence genes through their interactions with histone modifying proteins. The authors showed that two key histone modifiers, heterochromatin protein 1α (HP1α) and histone deacetylase 1 (HDAC1), associate with FRU at a number of chromosomal sites in a BON-dependent manner. Lowering the gene dosage of either of these proteins altered courtship behaviour in flies carrying loss-of-function mutations in fru: loss of Hp1a (also known as Su(var)205) increased male courtship behaviour, whereas loss of Hdac1 (also known as Rpd3) decreased it.

To investigate the role of these interactions in the formation of sexually dimorphic neural circuitry, the authors examined the effects of manipulating FRU, HP1α and HDAC1 levels on the mAL neuron cluster, which exhibits several sexually dimorphic features, including differences in the number of neurons and their axonal and dendritic morphology. Loss-of-function mutations in fru demasculinized the mAL cluster. This phenotype was exacerbated by knockdown of Hdac1 and alleviated by knockdown of Hp1a.

These findings suggest that FRU recruits chromatin modifying proteins that act to either masculinize (HDAC1) or feminize (HP1α) the neural circuitry that controls sex-specific behaviours. Further work will be required to identify the genes that are subject to this regulation and determine how the balance between the antagonistic effects of these two chromatin 'switches' is achieved.