Evolutionarily conserved sperm factors, DCST1 and DCST2, are required for gamete fusion

Abstract

To trigger gamete fusion, spermatozoa need to activate the molecular machinery in which sperm IZUMO1 and oocyte JUNO (IZUMO1R) interaction plays a critical role in mammals. Although a set of factors involved in this process has recently been identified, no common factor that can function in both vertebrates and invertebrates has yet been reported. Here, we first demonstrate that the evolutionarily conserved factors dendrocyte expressed seven transmembrane protein domain-containing 1 (DCST1) and dendrocyte expressed seven transmembrane protein domain-containing 2 (DCST2) are essential for sperm–egg fusion in mice, as proven by gene disruption and complementation experiments. We also found that the protein stability of another gamete fusion-related sperm factor, SPACA6, is differently regulated by DCST1/2 and IZUMO1. Thus, we suggest that spermatozoa ensure proper fertilization in mammals by integrating various molecular pathways, including an evolutionarily conserved system that has developed as a result of nearly one billion years of evolution.

The sperm protein Spaca6 is essential for fertilization in zebrafish

“…Together, this study and studies in mice point towards a coregulation of SPACA6 and DCST1/2. Inoue et al demonstrated that DCST1/2 regulates the levels of SPACA6 (Inoue et al, 2021) and we show that zebrafish Spaca6 regulates Dcst2 levels (Fig. 5).…”

“…Moreover, we have shown that DCST1 and DCST2 are also necessary for zebrafish fertilization (Noda et al, 2021). However, while in mice Dcst1 and Dcst2 KO sperm can bind to, but rarely fuse with oocytes (Inoue et al, 2021;Noda et al, 2021), zebrafish dcst1/2 KO sperm already show defects in sperm-egg binding (Noda et al, 2021). Therefore, zebrafish represents an interesting model system for the study of fertilization; despite the presence of mammalian fertilization factors in fish (Dcst1/2, Bouncer/SPACA4), the currently characterized factors show functional divergence in the fertilization process (Fujihara et al, 2021;Noda et al, 2021).…”

“…CD9, an integral membrane protein expressed on the oolemma, has also been shown to be required for gamete fusion (Kaji et al, 2000;le Naour et al, 2000;Miyado et al, 2000). Furthermore, other sperm factors -fertilization influencing membrane protein (FIMP), sperm-oocyte fusion required 1 (SOF1), transmembrane protein 95 (TMEM95), sperm acrosome associated 6 (SPACA6) and the DC-STAMP-like domain-containing proteins DCST1 and DCST2 -have been shown to be required for sperm-egg fusion in mice (Barbaux et al, 2020;Noda et al, 2020Noda et al, , 2021Inoue et al, 2021). Despite the many factors shown to be necessary for sperm-egg fusion, the combination of these factors appears not to be sufficient to drive fusion in a heterologous system.…”

Role of Integrins in Sperm Activation and Fertilization

“…Additionally, certain candidate proteins were ruled out (e.g., fertilin or CRISP1 [85]). Based on current research, Juno and CD9 on oocytes; and Izumo1, SPACA6, TMEM95, FIMP, SOF1, DCST1, and DCST2 on sperm (reviewed in [86]) are considered as fertilization-essential proteins in mammals [73,[87][88][89][90][91][92][93][94].…”

Same gene, opposite sexes: Sex-specific divergent expression of a gene required for vertebrate fertilization

“…The first-ever-identified pair of proteins essential for sperm–egg binding in mammals were IZUMO1 on the sperm ( 14 ) and JUNO on the egg ( 15 ) and, so far, this remains the only pair we know. Recently, more proteins displayed on the sperm were shown to be required for fertilization, and their identification is shedding light on the mysterious mechanism that underlies sperm–egg interaction ( 16 – 19 ). Nonetheless , it is unclear whether they have a binding partner on the egg membrane like IZUMO1, how they cooperate, or if they are involved in the formation of multimolecular complexes ( 20 ).…”