Sperm and oocyte communication mechanisms controlling C. elegans fertility

Abstract

During sexual reproduction in many species, sperm and oocyte secrete diffusible signaling molecules to help orchestrate the biological symphony of fertilization. In the Caenorhabditis elegans gonad, bidirectional signaling between sperm and oocyte is important for guiding sperm to the fertilization site and inducing oocyte maturation. The molecular mechanisms that regulate sperm guidance and oocyte maturation are being delineated. Unexpectedly, these mechanisms are providing insight into human diseases, such as amyotrophic lateral sclerosis, spinal muscular atrophy, and cancer. Here we review sperm and oocyte communication in C. elegans and discuss relationships to human disorders.

Figure 1. The C. elegans proximal gonad and reproductive tract

Oocytes secrete signals derived from PUFAs to regulate sperm guidance to the spermatheca, the site of fertilization. Recent data provide strong evidence that these sperm guidance signals are novel F-series prostaglandins (J. Edmonds, J. Prasain, and M. Miller, unpublished data). Sperm, in turn, secrete the protein hormone MSP to induce oocyte maturation and ovarian sheath cell contraction. The maturing oocyte signals for dilation of the spermathecal valve, promoting ovulation into the spermatheca.

Figure 2. Working model of the MSP signal transduction mechanism that controls oocyte maturation rates

MSP binds to multiple receptors (MSPRs) expressed on oocyte and sheath cell surfaces. The only identified MSP receptor to date is the VAB-1 Eph receptor. MSP binding to MSPRs stimulates a sheath G_αs-adenylate cyclase cascade that antagonizes sheath/oocyte gap junctional signaling. Downstream of these gap junctions in oocytes is the MPK-1 MAP Kinase. VAB-1 and possibly other MSPRs in oocytes regulate the activity of an NMDA-subtype glutamate receptor comprised of the NMR-1 subunit. Ca²⁺ influx through this glutamate receptor is thought to regulate UNC-43 CaMKII activity. UNC-43 functions redundantly to promote oocyte maturation, but the mechanism is not well understood. VAB-1 trafficking from the cell surface to recycling endosomes is important for regulating maturation rates. The inositol triphosphate receptor ITR-1 may act downstream of VAB-1 to inhibit MPK-1 activation. Red lines indicate inhibitory pathways, while blue lines indicate stimulatory pathways. See text for further details.

Figure 3. Domain organization of selected MSP domain-containing proteins in C. elegans and humans

The C. elegans genome encodes over sixty predicted proteins with an MSP domain, including approximately 28 MSPs and the VAP homolog VPR-1. The human genome encodes five predicted proteins with an MSP domain, including two VAP homologs. A P56S mutation (white box) in human VAPB MSP domain is associated with ALS and late-onset SMA. Recent evidence supports the model that animal VAP MSP domains are cleaved from the transmembrane regions and secreted (Tsuda et al., 2008). MSPs share approximately 20–25% identity with VAP MSP domains. MSP domains from human MOSPD proteins share limited sequence identity with MSPs and VAP MSP domains (<25%), but the presence of key highly conserved residues are consistent with inclusion in the MSP family (Marchler-Bauer et al., 2009). VAP homologs are found in fungi, plants, and animals. MSPs are highly conserved in diverse nematodes (>60% identity), but have not been identified outside of nematodes. Putative MOSPD2 homologs have been identified in mammals, chickens, zebrafish, Drosophila, and C. elegans (B0336.11).

Figure 4. Sperm guidance in C. elegans

(A) Sperm guidance is monitored in vivo using a novel tracking assay. When mitotracker-labeled males are mated to non-labeled hermaphrodites, sperm (red) accumulate at the spermatheca (yellow outline) over time. One hour after mating, over 93% of sperm have migrated from the vulva (yellow arrow) to the spermatheca. In some anesthetized hermaphrodites, sperm do not enter the spermatheca because the spermatheca-uterine valve is blocked. When wild-type males are mated to PUFA-deficient fat-2(wa17) mutant hermaphrodites, sperm fail to accumulate at the spermatheca efficiently (Kubagawa et al., 2006). (B) Sperm motility values are measured from time-lapse videos taken shortly after mating. Directional velocity toward the spermatheca is measured by creating a straight line through the uterus from the vulva to the spermatheca. A reversal is defined as occurring when the angle generated from a sperm trace during three consecutive 30s frames is less than 90 degrees. Motility values are from wild-type sperm (Kubagawa et al., 2006). (C) In mammals, the omega-6 PUFA arachidonic acid can be converted into prostaglandin F_2α by prostaglandin G/H synthase and prostaglandin F synthase. Numbers indicate carbon positions from the omega (ω) end. PG, prostaglandin.