FAM209 associates with DPY19L2, and is required for sperm acrosome biogenesis and fertility in mice.

Julio M. Castaneda,Zhifeng Yu,Darius J. Devlin,Yuhkoh Satouh,Martin M. Matzuk,Masahito Ikawa,Keisuke Shimada

doi:10.1242/jcs.259206

Julio M. Castaneda, Zhifeng Yu + Show 5 more

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https://doi.org/10.1242/jcs.259206

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Abstract

ABSTRACTInfertility afflicts up to 15% of couples globally each year with men a contributing factor in 50% of these cases. Globozoospermia is a rare condition found in infertile men, which is characterized by defective acrosome biogenesis leading to the production of round-headed sperm. Here, we report that family with sequence similarity 209 (Fam209) is required for acrosome biogenesis in mouse sperm. FAM209 is a small transmembrane protein conserved among mammals. Loss of Fam209 results in fertility defects that are secondary to abnormalities in acrosome biogenesis during spermiogenesis, reminiscent of globozoospermia. Analysis of the FAM209 proteome identified DPY19L2, whose human orthologue is involved in the majority of globozoospermia cases. Although mutations in human and mouse Dpy19l2 have been shown to cause globozoospermia, no in vivo interacting partners of DPY19L2 have been identified until now. FAM209 colocalizes with DPY19L2 at the inner nuclear membrane to maintain the developing acrosome. Here, we identified FAM209 as the first interacting partner of DPY19L2, and the second protein that is essential for acrosome biogenesis that localizes to the inner nuclear membrane.

Highlights

Infertility is the inability to conceive after one year of unprotected sex and afflicts up to 15% of couples worldwide (C.D.C., 2019; Thonneau et al, 1991; W.H.O., 2018)
We show that the novel gene, Fam209, is an evolutionary conserved, testis-specific gene only present in mammals, and that expression of this gene is detected at the RNA level at post-natal day 20 (P20)
Based on our cell expression data and the single cysteine in the N-terminal domain, it is possible that these paralogs are disulfide-linked

Summary

Introduction

Infertility is the inability to conceive after one year of unprotected sex and afflicts up to 15% of couples worldwide (C.D.C., 2019; Thonneau et al, 1991; W.H.O., 2018). Globozoospermia (round-headed sperm) is a rare condition characterized by defects in acrosome biogenesis during spermiogenesis (Kullander and Rausing, 1975; Schirren Sen et al, 1971). Cytoskeletal proteins (F-actin, keratin 5) contribute for formation of a complex called the acroplaxome, an electron dense structure sandwiched between the inner acrosome membrane and the outer nuclear envelope that anchors the acrosome in proximity to the nucleus (Kierszenbaum et al, 2003). DPY19L2 was the first inner nuclear envelope protein shown to be essential for anchoring the acrosome to the nucleus and has been implicated in the majority of globozoospermia patients analyzed (Koscinski et al, 2011; Pierre et al, 2012). We report on the discovery of FAM209 as the second inner nuclear membrane protein required for acrosome biogenesis. We characterize two deleterious mutations in mouse Fam209 generated by CRISPR/Cas and implicate Fam209 as essential for acrosome biogenesis

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