The research team of Ying Shen, Yihong Yang and Xiaohui Jiang has published the latest research results entitled "Cep128 is involved in Spermatogenesis in humans and mice" in Nature Communications recently. Ying Shen is an associate researcher at theKey Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University. Yihong Yang is deputy chief physician of the Reproduction Medical Centre, West China Second University Hospital, and Xiaohui Jiang is chief physician of the Human Sperm Bank, West China Second University Hospital.

The research team identifieda homozygous missense CEP128  variant in two affected siblings with cryptozoospermia.“We further generated a mouse model harboring the orthologous missense variant of CEP128 in human cases via CRISPR-Cas9 gene editing, and the homozygous Cep128  knock-in (KI) mice exhibited reduced sperm counts and spermatozoa with morphological abnormalities. Intriguingly, the male Cep128 knock-out (KO) mice were infertile due to impaired spermatogenesis. These data show that CEP128 plays a crucial role in male fertility. Mechanistically, proteomics analysis on the testes of Cep128 KO and KI mice suggested that CEP128 is a functional protein with an essential role in the reproductive process by regulating expressions of Wbp2nl, Rcbtb2, Prss55, Crisp1, Defb22, Sun5, Tssk4, phosphorylated-Rbl1 (p-Rbl1), p-Gata4, and p-Trim33, which are associated with sperm accessory structure and fertilization process.”(introduction)

A. Dislocated arrangements of MTDs 1‒3 and ODFs 1‒3 were exhibited in the majority of the midpieces. ODF outer dense fibers, MTD peripheral microtubule doublets. (n = 3 biologically independent WT mice or KI mice; scale bars, 150 nm). b Impaired development of the connecting piece during spermiogenesis in male homozygous Cep128  KO and KI mice. In spermatid steps 9–14, PCs with incomplete structure were present in both male homozygous KO and KI mice. Signs of defective Sc formation were occasionally visible in spermatids from male homozygous KI mice, but not in KO mice. In contrast, the Bp was almost normal in both male homozygous KO and KI mice. PC proximal centriole, Sc segmented column, Bp basal plate. (n = 3 biologically independent WT mice, KO mice or KI mice; scale bars, 500 nm).

“Centrosomal proteins are necessary components of the centrosome, a conserved eukaryotic organelle essential to the reproductive process. However, few centrosomal proteins have been genetically linked to fertility. Herein we identify a homozygous missense variant of CEP128  (c.665 G > A [p.R222Q]) in two infertile males. Remarkably, male homozygous knock-in mice harboring the orthologous CEP128^R222Q  variant show anomalies in sperm morphology, count, and motility. Moreover, Cep128  knock-out mice manifest male infertility associated with disrupted sperm quality. We observe defective sperm flagella in both homozygous Cep128 KO and KI mice; the cilia development in other organs is normal—suggesting that CEP128  variants predominantly affected the ciliogenesis in the testes. Mechanistically, CEP128 is involved in male reproduction via regulating the expression of genes and/or the phosphorylation of TGF-β/BMP-signalling members during spermatogenesis. Altogether, our findings unveil a crucial role for CEP128 in male fertility and provide important insights into the functions of centrosomal proteins in reproductive biology.” (Abstract)