Abstract
The fusion of gamete membranes during fertilization is an essential process for sexual reproduction. Despite its importance, only three proteins are known to be indispensable for sperm-egg membrane fusion: the sperm proteins IZUMO1 and SPACA6, and the egg protein JUNO. Here we demonstrate that another sperm protein, TMEM95, is necessary for sperm-egg interaction. TMEM95 ablation in mice caused complete male-specific infertility. Sperm lacking this protein were morphologically normal exhibited normal motility, and could penetrate the zona pellucida and bind to the oolemma. However, once bound to the oolemma, TMEM95-deficient sperm were unable to fuse with the egg membrane or penetrate into the ooplasm, and fertilization could only be achieved by mechanical injection of one sperm into the ooplasm, thereby bypassing membrane fusion. These data demonstrate that TMEM95 is essential for mammalian fertilization.
Highlights
In sexually reproducing species, life begins with the fusion of two gametes during fertilization
TMEM95 coding region was located in a 1386 kb segment of extended homozygosity in 40 sub-fertile bulls identified in a Genome Wide Association Study carried out on the Fleckvieh breed population (Pausch et al, 2014)
In silico protein folding analysis shows that TMEM95 protein contains a single transmembrane domain and a secondary structure formed by bhairpin and a-helix which is remarkably similar to that found on IZUMO1 protein and termed ‘IZUMO1 domain’ (Ellerman et al, 2009), thereby suggesting a possible role in sperm-egg fusion (Figure 1A)
Summary
Life begins with the fusion of two gametes during fertilization. Only three proteins have been demonstrated to be essential for sperm-egg membrane interaction: the sperm proteins IZUMO1 (Inoue et al, 2005) and SPACA6 (Lorenzetti et al, 2014), and the egg protein JUNO (Bianchi et al, 2014). The ablation of another egg protein, CD9 (Kaji et al, 2000; Le Naour et al, 2000; Miyado et al, 2000), leads to a significant impairment in sperm-egg membrane fusion, but its ablation does not cause complete infertility. Very recently, the ablation of the sperm protein FIMP has been reported to cause severe subfertility due to gamete fusion defects (Fujihara et al, 2020)
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