Apoptosis in the fetal testis eliminates developmentally defective germ cell clones

Abstract

Many germ cells (GCs) are eliminated during development, long before differentiating to egg or sperm, but it is not clear why. Here, we examined how GC composition in the mouse fetal testis is altered by scheduled apoptosis during sex differentiation. Multicolored-lineage tracing revealed that apoptosis affects clonally-related GCs, suggesting that this fate decision occurs autonomously based on shared intrinsic properties. We identified extensive transcriptional heterogeneity among fetal GCs including an apoptosis-susceptible subpopulation delineated by high Trp53 and deviant differentiation. Alternatively, the GC subpopulation most likely to survive was advanced in differentiation. These results indicate that GC developmental fate is based upon discrete and cell-heritable fitnesses and imply that a dichotomy between sex-differentiation and apoptosis coordinates the removal of developmentally incompetent cells to improve gamete quality. Evidence that GC subpopulations are in different epigenetic states suggests that errors in epigenetic reprogramming form the basis of aberrant differentiation and apoptotic selection.

Proper timing of a quiescence period in precursor prospermatogonia is required for stem cell pool establishment in the male germline

“…A wave of apoptosis in the prospermatogonial population is known to occur during perinatal development and has been speculated to eliminate aberrant cells (Bejarano et al, 2018;Nguyen et al, 2019;Wang et al, 1998). Indeed, recent demonstrated that prospermatognia with developmentally defective genetic and epigenetic integrity are eliminated by apoptosis in the mouse (Nguyen et al, 2020). Based on results of the current study that showed massive apoptosis of prospermatogonia lacking RB1 activity and therefore abnormal cell cycle regulation during fetal development, we speculate that correct timing of mitotic arrest is an indicator of proper fitness that saves cells from apoptosis and disruption of this timing leads to elimination of cells that would normally contribute to the spermatogenic lineage in postnatal life.…”

“…Features of germline development are highly conserved among mammals, and stringent maintenance of genetic integrity is crucial for proper inheritance regardless of species (Barton et al, 2016;Hamer and de Rooij, 2018;Murphey et al, 2013). During germ cell development, apoptosis that occurs at both fetal and postnatal ages is believed to select for the most robust cells to persist into adulthood and generate gametes that will pass genetic information to the next generation (Bejarano et al, 2018;Nguyen et al, 2020;Wang et al, 1998). The mechanisms for biosensing of germ cell fitness are largely unknown, but apoptosis is generally required to maintain reproductive fitness through the removal of developmentally incompetent or 'undesirable' cells, thereby ultimately ensuring maintenance of gamete quality (Aitken et al, 2011;Nguyen et al, 2020;Runyan et al, 2006).…”

“…During germ cell development, apoptosis that occurs at both fetal and postnatal ages is believed to select for the most robust cells to persist into adulthood and generate gametes that will pass genetic information to the next generation (Bejarano et al, 2018;Nguyen et al, 2020;Wang et al, 1998). The mechanisms for biosensing of germ cell fitness are largely unknown, but apoptosis is generally required to maintain reproductive fitness through the removal of developmentally incompetent or 'undesirable' cells, thereby ultimately ensuring maintenance of gamete quality (Aitken et al, 2011;Nguyen et al, 2020;Runyan et al, 2006). In the current study, we discovered that disruption of the normal developmental timing of when prospermatogonia enter quiescence leads to apoptosis and complete germline ablation.…”

“…Owing to the asynchronous nature of germ cell development and heterogeneity of gene expression in wild-type cells at the embryonic/fetal age points of E12.5-18.5 (Law et al, 2019;Nguyen et al, 2019Nguyen et al, , 2020, we first aimed to explore whether disruption of entry to mitotic arrest on a normal timeline alters transcriptome profiles throughout the prospermatogonial population. Using a method of comprehensive integration, we aligned the six libraries followed by uniform manifold approximation projection (UMAP) and graph-based clustering to capture germ cell heterogeneity at E14.5 (Fig.…”

Germ cell determination and the developmental origin of germ cell tumors

“…Simultaneously deleting Bax results in bilateral tumors in all 129strain males (Nicholls et al, 2019). Deletion of Bax enables the survival of cells with a delayed or arrested development, and it increases the incidence of teratomas in mice carrying the Ter mutation (Cook et al, 2009(Cook et al, , 2011Nguyen et al, 2020).…”