Mechanisms of TGFß in prostaglandin synthesis and sperm guidance in Caenorhabditis elegans

Abstract

Background: The transparent epidermis of Caenorhabditis elegans makes it an attractive model to study sperm motility and migration within an intact reproductive tract. C elegans synthesize specific F-series prostaglandins (PGFs) that are important for guiding sperm toward the spermatheca. These PGFs are synthesized from polyunsaturated fatty acid (PUFA) precursors, such as arachidonic acid (AA), via a novel pathway, independent of the classical cyclooxygenases (Cox) responsible for most PG synthesis. While the enzyme(s) responsible for PG synthesis has yet to be identified, the DAF-7 TGFß pathway has been implicated in modulating PG levels and sperm guidance.Results: We find that the reduced PGF levels in daf-1 type I receptor mutants are responsible for the sperm guidance defect. The lower level of PGs in daf-1 mutants is due in part to the inaccessibility of AA. Finally, lipid analysis and assessment of sperm guidance in daf-1;daf-3 double mutants suggest DAF-3 suppresses PG production and sperm accumulation at the spermatheca. Our data suggest that DAF-3 functions in the nervous system, and possibly the germline, to affect sperm guidance. Conclusion:The C elegans TGFß pathway regulates many pathways to modulate PG metabolism and sperm guidance. These pathways likely function in the nervous system and possibly the germline.

Sperm-Guiding Unconventional Prostaglandins in C. elegans: Synthesis and Signaling

“…A chemotaxis-like mechanism is also reported in C. elegans, where PGs provide cues to the sperm to move towards the spermatheca for fertilization and this mechanism is regulated by TGF-β [13,54,89]. The response of each spermatozoan is uneven to the chemoattractants as evident from human and mouse spermatozoan chemotaxis studies [77,90].…”

“…Mutation in daf-7, the daf-1 and daf-4 receptors, or downstream daf-8 and daf-14 R-Smads results in sperm guidance defects and the defects can be rescued by the loss of antagonistic co-Smad daf-3 [14]. Recently, we have shown that reduced levels of PGs cause sperm guidance defects and suppression of daf-3 rescues the PG production as well as the sperm guidance defects in daf-1 mutants [89]. RNA sequencing results of WT, daf-1 and daf-1:daf-3 established the differential regulation of neuronal neurotransmitter transporters and ion channels genes [114].…”

“…Interestingly, feeding of PG precursor (i.e., AA) to daf-1 mutants failed to rescue the sperm guidance defects and PG synthesis. However, an in vitro chemical reaction between daf-1 lysate generated by lysing worm pellets and AA resulted in the production of PGF2α indicating that daf-1 mutants have machinery required for PG synthesis [89]. The reason for sperm guidance defect and low levels of PG in daf-1 mutants could be due in part to the inaccessibility of AA.…”