Abstract
The hermaphrodite germline of Caenorhabditis elegans initially engages in spermatogenesis and then switches to oogenesis during late stages of larval development. TRA-1, a member of the Ci/Gli family of transcriptional repressors, plays an essential role in this switch by repressing genes that promote spermatogenesis. WDR5 proteins are conserved components of histone methyltransferase complexes normally associated with gene activation. However, two C. elegans WDR5 homologs, wdr-5.1 and wdr-5.2 are redundantly required for normal TRA-1 dependent repression, and this function is independent of their roles in histone methylation. Animals lacking wdr-5.1/wdr-5.2 function fail to switch to oogenesis at 25°C, resulting in a masculinization of germline (Mog) phenotype. The Mog phenotype is caused by ectopic expression of fog-3, a direct target of TRA-1 repression. WDR-5.1 associates with the fog-3 promoter and is required for TRA-1 to bind to fog-3 promoter. Other direct targets of TRA-1 are similarly derepressed in the double mutant. These results show that WDR5 plays a novel and important role in stabilizing transcriptional repression during C. elegans sex determination, and provide evidence that this important protein may operate independently of its established role in histone methyltransferase complexes.
Highlights
Sex determination in the nematode Caenorhabditis elegans is genetically controlled by a complex negative regulatory pathway that is linked to the sex chromosome/autosome ratio [1]
We previously showed that mutations in the conserved histone methyltransferase complex component, wdr-5.1, cause a low penetrance masculinization of germline (Mog) phenotype in hermaphrodites [14], suggesting that wdr-5.1 and/or histone methylation play a role in germline sex determination
The absence of H3K4 methylation defects in the wdr-5.2 single mutant and the synthetic germ cell defects with wdr-5.1 suggested a redundancy in function for these two genes that is separate from WDR-5.1’s role in H3K4 methylation. We further investigate this additional role for WDR5 in germ cell development, and show that wdr-5.1 and wdr-5.2 are redundantly required for the switch from spermatogenesis to oogenesis in hermaphrodites to occur normally
Summary
Sex determination in the nematode Caenorhabditis elegans is genetically controlled by a complex negative regulatory pathway that is linked to the sex chromosome/autosome ratio [1]. The X:A ratio provides differing complementary doses of several X- and autosome-linked regulatory factors that control the expression of the master regulator xol-1, which regulates a cascade of negative genetic interactions that control sex determination and/or dosage compensation [1]. At the terminus of the sex determination cascade is TRA-1, a Zinc finger transcription factor, which plays a global role in determining the sexual identity of both germline and soma [4]. Ci/Gli proteins play pivotal roles in development, stem cell maintenance and tumorigenesis as transducers of Hedgehog signaling [7]. There is no known Hedgehog signaling pathway in C. elegans, it is proposed that the worm sex determination pathway was adapted or derived from the Hedgehog pathway [2]
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