Drosophila Pif1A is essential for spermatogenesis and is the homolog of human CCDC157, a gene associated with idiopathic NOA

Abstract

The dynamic process of spermatogenesis shows little variation between invertebrate models such as Drosophila, and vertebrate models such as mice and rats. In each case, germ stem cells undergo mitotic division to proliferate and then continue, via meiosis, through various stages of elongation and individualization from spermatogonia to spermatid to finally to form mature sperm. Mature sperm are then stored in the seminal vesicles for fertilization. Errors in any of these stages can lead to male infertility. Here, we identify that Drosophila Pif1A acts as a key regulator for sperm individualization. Loss of Pif1A leads to male sterility associated with irregular individualization complex and empty seminal vesicles without mature sperm. Pif1A is highly expressed in the testes of mated male adult flies and the Pif1A protein is expressed at a higher level in male than in female flies. Pif1A is homologous to mammalian coiled-coil domain-containing protein 157 (CCDC157), which is also enriched in the testes of humans and mice. Human CCDC157, with unknown function, was identified to be downregulated in men with idiopathic non-obstructive azoospermia (NOA). We map the function of Drosophila Pif1A during spermatogenesis, showing that Pif1A is essential for spermatide individualization and involved in the regulation of the lipid metabolism genes. Our findings might be applicable for studying the function of CCDC157 in spermatogenesis and other aspects of human male fertility.

PFTAIRE Kinase L63 Interactor 1A (Pif1A Protein) Is Required for Actin Cone Movement during Spermatid Individualization in Drosophila melanogaster

“…These authors report that Pif1A mutant flies develop actin cones, but the cones do not move, spermatid individualization fails and the flies are completely sterile. However, we note a few differences between our results and those of Yuan et al [ 17 ]. Firstly, they occasionally observed actin cones facing the wrong direction, which we have never seen.…”

“…Our data are largely in agreement with those of Yuan et al [ 17 ], who used CRISPR/Cas9 to create a frame shift nonsense mutation in the Pif1A gene. These authors report that Pif1A mutant flies develop actin cones, but the cones do not move, spermatid individualization fails and the flies are completely sterile.…”

“…The exact function of Pif1A during spermatogenesis is unclear at this point. Yuan et al [ 17 ] report that Pif1A is similar to the human gene coding CCDC157, which is associated with non-obstructive azoospermia. Additionally, they suggest that Pif1A protein is involved in regulating lipid metabolism genes, which could be important during spermatid membrane reorganization.…”

Weighted Correlation Gene Network Analysis Reveals New Potential Mechanisms and Biomarkers in Non-obstructive Azoospermia

“…Cell cycle and oocyte meiosis were the most significantly enriched pathways of DEGs in NOA. Indeed, DEGs can exert a non-negligible influence on each stage of meiotic progression, resulting in interrupted or incomplete spermatogenesis, or sperm maturation in this case ( Dorosh et al, 2013 ; Long et al, 2017 ; van der Bijl et al, 2019 ; Yuan et al, 2019 ; Wyrwoll et al, 2020 ). In the pathway enrichment analysis, we have obtained multiple pathways related to NOA.…”

Preliminary investigation of the function of hsa_circ_0049356 in nonobstructive azoospermia patients

“…Spermatogenesis is a polygenic and multistep process that involves a variety of regulatory molecules (Wang et al., 2018; Yuan et al., 2019). NOA represents the most severe male infertility condition, and various genetic anomalies have been reported to be involved in the progression of disease (Cervan‐Martin et al., 2020; Vogt et al., 2019).…”