Glycopeptide hormone signaling is crucial to the normal development and physiology of mammals. In humans, disruption of glycopeptide hormone signaling results in a variety of health defects, including infertility and hypothyroidism. The C. elegans gene
fshr-1 (follicle stimulating hormone receptor) encodes the single ancestral ortholog of three human glycopeptide hormone receptors: luteinizing hormone receptor (LHR), follicle stimulating hormone receptor (FSHR), and thyroid stimulating hormone receptor (TSHR). We have recently described a synthetic interaction whereby loss of function in
fshr-1 strongly enhances germline masculinization caused by partial knockdown of both
fbf-1 and
fbf-2 resulting from
fbf-1 RNAi feeding. We also found that a gain of function in
gsa-1, a G<font face=symbol>a</font>s subunit, significantly suppressed germline masculinization in
fshr-1;fbf(RNAi) animals. Further, a gain of function in
acy-1, the C. elegans adenyl cyclase, was also able to partially suppress germline masculinization, suggesting that, like its human orthologs,
fshr-1 acts through a canonical G-protein/adenyl cyclase signaling pathway. Our results demonstrate that suppression of germline masculinization in
fshr-1;fbf(RNAi) animals is possible and that identification of additional suppressors could reveal novel genes that function in glycopeptide hormone signaling. Based on these findings, we have screened for suppressors of
fshr-1;fbf(RNAi) sterility. To identify gain of function mutations in genes that positively regulate the
fshr-1 signaling pathway, as well as loss of function mutations in genes that negatively regulate the pathway,
fshr-1(0) mutants were mutagenized with EMS and their progeny subsequently picked to fbf RNAi plates. Plates containing suppressed (fertile) animals were identified, and suppressed animals were tested for RNAi sensitivity on
pos-1,
cye-1 and
unc-22 RNAi plates in order to eliminate RNAi insensitive mutants. Preliminary screens of ~7,000 haploid genomes have yielded 12 RNAi sensitive mutants that suppress sterility in
fshr-1;fbf(RNAi) animals. Penetrance of suppression in these animals varies from moderate (25-50%) to very strong (>90%). Several of these mutations seem to be dominant, and experiments are currently underway to further characterize these mutants genetically.