Reproduction is an intense energetic and physiological commitment requiring an organism to carefully balance the promise of offspring against the cost to its own survival. In my dissertation research in the laboratory of Dr. Siu Sylvia Lee (Cornell), I have dissected mechanisms that manage this trade-off in the nematode worm Caenorhabditis elegans, uncovering how somatic metabolic sensors act as critical gatekeepers to synchronize oocyte activation with systemic readiness. These studies collectively demonstrate how reproductive restraint maybe an actively enforced strategy by which the soma protects future fertility and, by extension, organismal longevity.

An evolutionarily conserved "oocyte quiescence" is critical for safeguarding reproductive potential until favorable conditions arise. Releasing oocytes prematurely wastes metabolic investment and, as my work shows, shortens organismal lifespan. In Chapter II of this dissertation (Gopal, Chaturbedi et al. Biorxiv. 2025), we investigated the phenomenon of active reproductive restraint. We discovered that in the absence of sperm, premature oocyte maturation is actively suppressed by a somatic metabolic checkpoint. We identified that the nuclear hormone receptor NHR-49/HNF4, a critical transcriptional regulator of lipid metabolism, acts in somatic gonadal sheath cells to enforce this restraint. We found that NHR-49 specifically represses GSA-1–driven MAPK activation, the critical signal that would otherwise trigger maturation, and thus actively prevents premature oocyte release. Collectively, these findings reposition NHR-49 from a metabolic transcription factor to a key systemic integrator of energy state and reproductive timing.

A parallel metabolic checkpoint is required to enforce germline arrest during periods of starvation, but the mechanisms linking nutrient status to this specific arrest were unclear. In Chapter III of this dissertation, we identified DAF-18, the C. elegans ortholog of PTEN, as a second checkpoint that enforces both sperm-dependent and starvation-induced germline arrest (Gopal, Ramachandrula et al. In preparation). We found that loss of DAF-18 abolishes this ovulatory quiescence and induces aberrant MAPK activity, leading to sustained oocyte release even under severe nutrient deprivation. Using tissue-specific analyses, we showed that DAF-18 acts non-autonomously from the soma to enforce this starvation checkpoint. These studies reveal a conserved axis through which PTEN family phosphatases integrate metabolic cues with germline restraint.

In Chapter IV I outline future directions to dissect the logic of this somatic surveillance, including identifying the specific ligands that activate NHR-49 and delineating the full DAF-18/PTEN signaling circuitry. Altogether, my studies define two critical and parallel somatic checkpoints, NHR-49 and DAF-18, that link metabolic surveillance to reproductive control. Moreover, the CUT&RUN, RNA-seq, and dissected-gonad transcriptomic datasets I have generated serve as critical resources for understanding and manipulating this fundamental somatic-germline communication.