Gamete interactions require transmembranous immunoglobulin-like proteins with conserved roles during evolution

Abstract

C. elegans spe-9 class genes are male germline-enriched in their expression and indispensable during sperm-oocyte fusion. Identification of mammalian orthologs that exhibit similar functions to these C. elegans genes has been a challenge. The mouse Izumo1 gene encodes a sperm-specific, immunoglobulin (Ig)-like transmembrane (TM) protein that is required for gamete fusion. We recently identified the C. elegans spe-45 gene, which shows male germline-enriched expression and encodes an Ig-like TM protein. spe-45 mutant worms produced otherwise normal spermatozoa that cannot fuse with oocytes, causing essentially the same phenotype as that seen in the Izumo1-knockout mice. By counting the number of self-sperm in the spermatheca of spe-45 hermaphrodites, it was found that this gene might be involved in sperm guidance from the uterus into the spermatheca, as well as gamete fusion. Moreover, we discovered that SPE-45 and IZUMO1 share certain functions for gamete fusion, which are presumably related to binding with cis-and/or trans-partners. Intriguingly, various organisms have Ig-like TM proteins that act during gamete interactions, indicating the wide-spread utility of Ig-like domains during fertilization.

MAR1 links membrane adhesion to membrane merger during cell-cell fusion in Chlamydomonas

“…The Immunoglobulin Superfamily (IgSF) is large and diverse, and many of its members function in intercellular adhesion in prokaryotes and eukaryotes (Chatterjee et al, 2020; Honig and Shapiro, 2020). Several proteins important for sperm-egg interactions in metazoans possess Ig-like domains (Nishimura and L’Hernault, 2016), the best characterized being the sperm adhesion protein IZUMO1, whose single Ig-like domain forms a portion of the interface between IZUMO1 and its egg binding partner, JUNO (Aydin et al , 2016; Ohto et al , 2016). The previously reported presence of Ig-like domains in Chlamydomonas FUS1 (Misamore et al , 2003) and plant GEX2 (Mori et al , 2014) proteins called further attention to the widespread use these domains in sexual reproduction.…”

The molecular underpinnings of fertility: Genetic approaches in Caenorhabditis elegans

“…elegans was identified not only in our mutant hunt, but also independently by a reverse genetic approach searching for single‐Ig domain containing, sperm‐surface molecules like IZUMO1 24 . In addition to identical phenotypes of in both the worm and mouse, chimeric SPE‐45 with the mouse IZUMO1 Ig domain expressed as a transgene partially rescued the spe‐45 mutant fertility, suggesting conserved functions of the Ig domain 24,105 . The discovery of C .…”

“…24 In addition to identical phenotypes of in both the worm and mouse, chimeric SPE-45 with the mouse IZUMO1 Ig domain expressed as a transgene partially rescued the spe-45 mutant fertility, suggesting conserved functions of the Ig domain. 24,105 The discovery of C. elegans spe-51 as an Ig-like fold containing protein further highlights important functions of Ig domains at the fertilization synapse.…”

“… 24 In addition to identical phenotypes of in both the worm and mouse, chimeric SPE-45 with the mouse IZUMO1 Ig domain expressed as a transgene partially rescued the spe-45 mutant fertility, suggesting conserved functions of the Ig domain. 24 , 105 The discovery of C. elegans spe-51 as an Ig-like fold containing protein further highlights important functions of Ig domains at the fertilization synapse. The fact that shared protein domains are utilized to achieve the same reproductive goal in two evolutionarily distant species suggests a deep conservation of protein structures at the gamete interface despite rapid co-evolution of gamete-interacting proteins.…”

SPE-51, a sperm secreted protein with an Immunoglobulin-like domain, is required for sperm-egg fusion inC. elegans

“…Disruptions of both Izumo1 and Spaca6 result in male sterility with mutant spermatozoa being able to migrate into the oviduct, to undergo acrosome reaction and to penetrate the zona pellucida but unable to fertilize the egg (Inoue et al, 2005;Lorenzetti et al, 2014). These phenotypes strongly resemble those of the spe-45 or spe-51 mutants, suggesting that Ig superfamily proteins may have an evolutionarily conserved role during fertilization (Nishimura and L'Hernault, 2016;Tajima and Nishimura, 2018).…”