Towards Post-Meiotic Sperm Production: Genetic Insight into Human Infertility from Mouse Models

Abstract

Declined quality and quantity of sperm is currently the major cause of patients suffering from infertility. Male germ cell development is spatiotemporally regulated throughout the whole developmental process. While it has been known that exogenous factors, such as environmental exposure, diet and lifestyle, et al, play causative roles in male infertility, recent progress has revealed abundant genetic mutations tightly associated with defective male germline development. In mammals, male germ cells undergo dramatic morphological change (i.e., nuclear condensation) and chromatin remodeling during post-meiotic haploid germline development, a process termed spermiogenesis; However, the molecular machinery players and functional mechanisms have yet to be identified. To date, accumulated evidence suggests that disruption in any step of haploid germline development is likely manifested as fertility issues with low sperm count, poor sperm motility, aberrant sperm morphology or combined. With the continually declined cost of next-generation sequencing and recent progress of CRISPR/Cas9 technology, growing studies have revealed a vast number of disease-causing genetic variants associated with spermiogenic defects in both mice and humans, along with mechanistic insights partially attained and validated through genetically engineered mouse models (GEMMs). In this review, we mainly summarize genes that are functional at post-meiotic stage. Identification and characterization of deleterious genetic variants should aid in our understanding of germline development, and thereby further improve the diagnosis and treatment of male infertility.

Targeted mutation and inactivation of the kinesin light chain 3 protein-encoding gene have no impact on mouse fertility

“…When it comes to sex differentiation and germline development, the situation is more nuanced. Overall, the genetic pathways controlling these events appear largely conserved between the two species but differences were identified ( [33][34][35] for recent reviews). For example, the function of DMRT1 in male-and of the FOXL2 in female-gonadal differentiation in humans is not conserved in mice, but exists in other mammalian species [36,37].…”

Oral thymoquinone modulates cyclophosphamide‐induced testicular toxicity in adolescent Wistar rats

“…For viable spermatozoa with the reproductive capability to be produced, spermatogenesis must go unhindered and undisturbed. An insult to the body or specifically directed at the reproductive organs, such as the testes, could distort spermatogenesis and impair reproductive functions in males, due to the poor quality and characteristics of sperm cells (Azhar et al, 2021; Badkoobeh et al, 2013; Omotoso et al, 2017; Tvrdá et al, 2021).…”

Genetic control of meiosis surveillance mechanisms in mammals

“…However, it is essential to point out that we must be cautious when using the findings from mouse studies to interpret the causative factors and mechanisms underlying human infertility regarding considerable differences still exist between humans and mice (Azhar et al, 2021). A recent study has shown that the metaphase checkpoint is more frequently activated than the pachytene checkpoint in human males with severe spermatogenic impairment (Enguita-Marruedo et al, 2019), which is in contrast to observations in the mouse, where knockout of the meiotic prophase genes (as we summarized above) most frequently results in pachytene checkpoint arrest.…”