Tsga8 is required for spermatid morphogenesis and male fertility in mice

Abstract

During spermatogenesis, intricate gene expression is coordinately regulated by epigenetic modifiers, which are required for differentiation of spermatogonial stem cells (SSCs) contained among undifferentiated spermatogonia. We previously found that KMT2B conveys H3K4me3 at bivalent and monovalent promoters in undifferentiated spermatogonia. Because these genes are expressed late in spermatogenesis or during embryogenesis, we expect that many of them are potentially programmed by KMT2B for future expression. Here, we show that one of the genes targeted by KMT2B, Tsga8, plays an essential role in spermatid morphogenesis. Loss of Tsga8 in mice leads to male infertility associated with abnormal chromosomal distribution in round spermatids, malformation of elongating spermatid heads and spermiation failure. Tsga8 depletion leads to dysregulation of thousands of genes, including the X chromosome genes that are reactivated in spermatids, and insufficient nuclear condensation accompanied by reductions of TNP1 and PRM1, key factors for histone-to-protamine transition. Intracytoplasmic sperm injection (ICSI) of spermatids rescued the infertility phenotype, suggesting competency of the spermatid genome for fertilization. Thus, Tsga8 is a KMT2B target that is vitally necessary for spermiogenesis and fertility.

Identification and characterization of dystrophin-locus-derived testis-specific protein: A testis-specific gene within the intronic region of the rat dystrophin gene

“…Recently, Kobayashi et al . [ 22 ] revealed that Tsga8 is required for spermatid morphogenesis in mice. Although no clear orthologs of mouse Tsga8 have been found in other mammalian species, a highly divergent hypothetical gene has been identified within the genomic region containing the rat dystrophin gene [ 11 ].…”

“…Kobayashi et al . [ 22 ] previously established the crucial role of mouse Tsga8 , a putative ortholog of rat Dtsp , in spermiogenesis, particularly in proper spermatid morphogenesis. The testicular phenotype exhibited by BMD rats closely mirrors that of Tsga8 -deficient mice.…”

“…However, the severity of outcomes resulting from the loss of DTSP (TSGA8 in mice) differs significantly between rats and mice. In mice, the absence of TSGA8 results in abnormal spermatid morphology at 3 months of age, with spermatids still present in the seminiferous tubules [ 22 ]. In contrast, in BMD rats, the absence of DTSP leads to an almost complete loss of both spermatocytes and spermatids at 3 months of age, along with defects in Sertoli cells, characterized by abnormal cytoplasmic spreading.…”

The expression, function, and utilization of Protamine1: a literature review

“…With the intra-and inter-molecular disulfide crosslinks formed by cysteine residues in PRM1, the characteristic toroidal structures are created and each contains roughly 50 kb of DNAs. This binding between PRM1, PRM2 and DNA backbone leads to the remarkable compression of approximately 85% of chromatins which are finally stored in the sperm head, and a small proportion of histones is retained which plays important roles after fertilization (32)(33)(34). These processes guarantee the unharmed transferring of the paternal genetic information to the oocyte and assure that the genetic information can be properly accessed by the developing embryo (1).…”

Inhibition of p38MAPK signalling pathway alleviates radiation‐induced testicular damage through improving spermatogenesis

“…Radiotherapy is an effective treatment for many tumours. About 60% of patients with newly diagnosed cancers have radiotherapy as their first-line treatment (Kobayashi et al, 2021). Radiotherapy can significantly improve survival in cancer patients and the survival of children with cancer has increased to 84% due to the emergence of effective cancer therapy (Karim-Kos et al, 2016).…”