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.

Keywords: Spermiogenesis; genetically engineered mouse model (GEMM); infertility; oligoasthenoteratozoospermia (OAT); spermatogenesis.

Figure 1

Schematic diagram illustrating a total of 16 steps of haploid germline development in mice. Spermiogenesis is categorized into four phases (Golgi phase, Cap phase, Acrosome phase and Maturation phase) according to the acrosome morphology. Conventionally, spermatids are divided into 16 steps on basis of acrosome and head morphology, and the criteria is commonly leveraged to pinpoint the specific step of spermiogenic arrest through H&E staining of the sections from GEMMs. In literature, spermatids are often classified into four groups based on nuclear morphology: round spermatids (Steps 1~8), elongating/condensing spermatids (Steps 9~11), elongated/condensed spermatids (Step 12~14) and spermatozoa (Step 15~16). Representative genes essential for spermatid development are listed at the bottom.

Figure 2

Schematic illustration of the ultrastructure of mature mouse sperm. Sperm flagellum is structurally divided into three parts - midpiece, principal piece, and end piece; Each part comprises the core axoneme, which is composed of the canonical “9+2” arrangement of microtubules, in the center. The vertical arrow points to the #1 pair of microtubules while the horizontal dash line parallels the central pair of microtubules, in the cross mark. The mitochondrial sheath and the outer dense fibers (ODFs) wrap around the mid-piece and principal piece, respectively. The connection part between sperm head and tail is the neck, also termed head-tail coupling apparatus or connecting piece (right panel) , .

Figure 3

Schematic representation of morphological abnormalities of sperm in mice and humans. A. Comparison of normal sperm head morphology between mouse and human; B. Common types of aberrant morphologies of sperm in mice and humans.