Sec61β Deficiency Disrupts Drosophila Oogenesis Through UPR-Mediated Defects in Germ Cell Proliferation and Differentiation

Cbx3a/HP1γ Deficiency Disrupts Meiotic Progression and Triggers Germ Cell Apoptosis in Nile Tilapia

The essential and conserved role of Cbx3a/HP1γ in Nile tilapia spermatogenesis is clarified, thereby advancing the field of vertebrate reproductive epigenetics and providing a valuable theoretical basis for potential applications in reproductive management, such as improving sperm quality.

Apoptosis promotes fertility in Caenorhabditis elegans by maintaining functional germline morphology

ABSTRACT Programmed cell death (apoptosis) during oogenesis is conserved across metazoans and linked to regulation of oocyte number and quality. In oogenic germlines, the removal of developing oocytes by apoptosis ensures that oocytes do not contain DNA damage or multiple nuclei. Beyond this chromatin-quality control assurance role, it was unknown how apoptosis contributes to oocyte quality. We used the nematode Caenorhabditis elegans to study the consequences of loss of apoptosis on oogenesis. Blocking apoptosis reduced fecundity in hermaphrodites at peak fertility and caused germline architectural defects, such as abnormal rachis morphology and perturbed arrangement and distribution of oogenic germline compartments. Our results suggest that the loss of germline apoptosis arises due to lack of sufficient space for, and reduced cytoplasmic flows into, developing oogonia. In support of this idea, oocytes and embryos are abnormally small and exhibit low viability in animals unable to execute apoptosis. These findings suggest that, in addition to preventing ploidy defects during oogenesis, apoptosis contributes to fertility by preserving the homeostatic germline structure required for the fidelity of oogenesis.

Developmentally-regulated post-apocrine cell death of Drosophila salivary glands utilizes ER stress-linked apoptosis

The Drosophila salivary glands (SGs) are highly specialized secretory organs that provide an ideal model to study developmentally-associated programmed cell death (PCD), as they respond to the steroid hormone ecdysone to undergo programmed histolysis during larval-to-adult metamorphosis. Understanding the mechanism underlying PCD is a prerequisite to investigating how its timing is coordinated with a massive apocrine secretion that concludes just hours earlier. Here we show that SG apoptosis is linked to endoplasmic reticulum (ER) disintegration via an ER-stress mechanism. Depletion of ER calcium stores was very effective at inducing ER vesiculation and subsequent cell death. Depletion led to the activation of Xbp1, implicating the involvement of unfolded protein response (UPR) signaling. Genetic manipulation of ER-resident proteins, chaperones and co-chaperones resulted in a widespread and fast vesiculation of the ER, typical of that seen during the final apoptotic stage in wild type animals. In contrast, the genetic removal of the SERCA pump prevented SG apoptosis. Being the largest organelle in the SG, the ER is able to provide for a robust and extremely fast spread of cell-death signals. Since malfunction of any of the mentioned proteins led to a fast apoptotic response, either each can function as sensor of an ER apoptotic pathway, or their action converges onto a common sensor to provide a universal signal to initiate a cascade leading to rapid caspase activation and ER vesiculation.

Cth1 is essential for gametogenesis and fertility in zebrafish

Infertility frequently arises from defects in germ cells and early embryonic transition. Successful fertilization depends on the developmental competence and molecular integrity of mature gametes from both parents, which are established through tightly coordinated programs of RNA regulation, metabolism, and genome maintenance. In our previous work, we identified Cth1 as a maternally regulated RNA-decay factor essential for early embryonic development, acting through spatiotemporal control of maternal transcript clearance. Interestingly, Cth1 loss of function in adults also resulted in infertility, suggesting an additional and unexplored role during gametogenesis. Here, we extend these findings by defining the gametogenic function of Cth1 in zebrafish. Through detailed phenotypic, cytological and molecular characterization of Cth1 loss-of-function mutants, we show that Cth1 is highly enriched in germ cells and early embryos and is spatio-temporally localized across oogenesis and early development. Loss of Cth1 causes severe defects in early oogenesis and spermatogenesis, resulting in complete infertility in males and females. Mutant germ cells display transcriptomic changes consistent with metabolic and translational dysregulation, increased DNA damage, and striking abnormalities in gamete morphology. Together, these findings identify Cth1 as essential for gamete quality and fertility. Our study suggests a link between RNA decay–mediated regulation of metabolism and genome integrity during germ cell development and reveals disruption of post-transcriptional control as a potential mechanism underlying infertility. Highlights xxxx

Terno, a cyclin-interacting protein regulating meiotic exit and sperm differentiation in Drosophila.

Insufficiency of cohesin regulatory protein PDS5B triggers meiotic failure and aneuploidy in oocytes during advanced maternal aging.

Oocytes rely on a cohort of proteins whose sustained expression ensures normal meiotic progression and reproductive competence throughout an animal's reproductive life. Age-related declines in these proteins are a major cause of reduced oocyte quality and female fertility during reproductive aging. Here, we report that the cohesin regulatory protein PDS5B, a dynamically maintained factor in oocytes, declines with age and plays a noncanonical role in the spindle pole formation independent of its cohesion function during oocyte meiotic maturation. Specifically, we found that PDS5B was expressed throughout the oocyte meiosis and localized at the spindle poles at metaphase stages, while its protein abundance was reduced in aged oocytes, concomitant with decreased messenger ribonucleic acid (mRNA) levels and translational efficiency. Knockdown or heterozygous knockout of PDS5B caused spindle assembly defects, meiotic arrest, and aneuploidy in oocytes, ultimately leading to female subfertility. Mechanistically, immunoprecipitation/mass spectrometry analyses revealed that PDS5B recruited deubiquitinating enzyme USP9X to spindle poles to stabilize nuclear mitotic apparatus and promote proper spindle assembly. Moreover, expression of exogenous PDS5B in aged oocytes partially alleviated meiotic defects associated with advanced maternal age. Altogether, our findings uncover a unique spindle pole-specific function of PDS5B in oocytes and suggest that maintaining PDS5B levels may be a potential strategy to improve the quality of aged oocytes.