Partial proteasomal degradation of Lola triggers the male-to-female switch of a dimorphic courtship circuit

Abstract

In Drosophila, some neurons develop sex-specific neurites that contribute to dimorphic circuits for sex-specific behavior. As opposed to the idea that the sexual dichotomy in transcriptional profiles produced by a sex-specific factor underlies such sex differences, we discovered that the sex-specific cleavage confers the activity as a sexual-fate inducer on the pleiotropic transcription factor Longitudinals lacking (Lola). Surprisingly, Fruitless, another transcription factor with a master regulator role for courtship circuitry formation, directly binds to Lola to protect its cleavage in males. We also show that Lola cleavage involves E3 ubiquitin ligase Cullin1 and 26S proteasome. Our work adds a new dimension to the study of sex-specific behavior and its circuit basis by unveiling a mechanistic link between proteolysis and the sexually dimorphic patterning of circuits. Our findings may also provide new insights into potential causes of the sex-biased incidence of some neuropsychiatric diseases and inspire novel therapeutic approaches to such disorders.

The mode of action of Fruitless: Is it an easy matter to switch the sex?

“…Large Lola-Q represses the robo1 reporter transcription in S2 cells, whereas small Lola-Q counteracts large Lola-Q. 48 Consistent with such synergy at the molecular level, overexpression of large Lola-Q mitigates cellular phenotypes of fru loss-of-function; e.g., it restores the male-specific neurite otherwise lost in fru mutant males ( Figure 4C). Reporter assays in S2 cells showed a synergistic action between large Lola-Q and FruBM in repressing transcription from the robo1 promoter.…”

“…Reporter assays in S2 cells showed a synergistic action between large Lola-Q and FruBM in repressing transcription from the robo1 promoter. 48 Consistent with such synergy at the molecular level, overexpression of large Lola-Q mitigates cellular phenotypes of fru loss-of-function; e.g., it restores the male-specific neurite otherwise lost in fru mutant males ( Figure 4C). This activity of large Lola-Q to rescue the male-specific neurite in fru mutant males is abrogated by simultaneous overexpression of small Lola-Q ( Figure 4D), in keeping with the inhibitory effect of small Lola-Q on large Lola-Q at the molecular level (see above).…”

“…Reporter assays in S2 cells showed a synergistic action between large Lola-Q and FruBM in repressing transcription from the robo1 promoter. 48 At the behavioral level, deletion of DR1 in the robo1 promoter (robo1 Δ4 ; shown in Sato et al 48 ) induces precocious wingswitching during male courtship reminiscent of the phenotype in flies that carry robo1 Δ1 . This activity of large Lola-Q to rescue the male-specific neurite in fru mutant males is abrogated by simultaneous overexpression of small Lola-Q ( Figure 4D), in keeping with the inhibitory effect of small Lola-Q on large Lola-Q at the molecular level (see above).…”

“…This activity of large Lola-Q to rescue the male-specific neurite in fru mutant males is abrogated by simultaneous overexpression of small Lola-Q ( Figure 4D), in keeping with the inhibitory effect of small Lola-Q on large Lola-Q at the molecular level (see above). 48 48 At the behavioral level, deletion of DR1 in the robo1 promoter (robo1 Δ4 ; shown in Sato et al 48 ) induces precocious wingswitching during male courtship reminiscent of the phenotype in flies that carry robo1 Δ1 .…”

“…Because many BTB-zinc finger proteins interact via each other's BTB domain, 47 it is tempting to postulate that FruBM and Lola form a complex to regulate transcription of their shared target genes. Sato et al 48 discovered that isoform-Q is composed of two distinct molecules with different molecular weights, that is, small Lola-Q enriched in females and large Lola-Q with male-biased expression ( Figure 4A,B). Large Lola-Q represses the robo1 reporter transcription in S2 cells, whereas small Lola-Q counteracts large Lola-Q.…”