Distinct Roles and Synergistic Function of Fru^M Isoforms in Drosophila Olfactory Receptor Neurons

Sexual dimorphism in Drosophila courtship circuits requires the male-specific transcription factor fru^M, which is alternatively spliced to encode the Fru^MA, Fru^MB, and Fru^MC isoforms. Most fru^M-positive neurons express multiple variants; however, the functional significance of their co-expression remains undetermined. Do co-expressed isoforms each play unique roles to jointly regulate dimorphism? By focusing on fru^M-positive olfactory receptor neurons (ORNs), here, we show that Fru^MB and Fru^MC are both required for males' age-dependent sensitization to aphrodisiac olfactory cues in a cell-autonomous manner. Interestingly, Fru^MB expression is upregulated with age in Or47b and Ir84a ORNs, and its overexpression mimics the effect of age in elevating olfactory responses. Mechanistically, Fru^MB and Fru^MC synergistically mediate response sensitization through cooperation of their respective downstream effectors, namely, PPK25 and PPK23, which are both required for forming a functional amplification channel in ORNs. Together, these results provide critical mechanistic insight into how co-expressed Fru^M isoforms jointly coordinate dimorphic neurophysiology.