Mouse Sperm Lacking ADAM1b/ADAM2 Fertilin Can Fuse with the Egg Plasma Membrane and Effect Fertilization

Abstract

Fertilin, a heterodimeric protein complex composed of ␣ (ADAM1) and ␤ (ADAM2) subunits on the sperm surface, is believed to mediate adhesion and fusion between the sperm and egg plasma membranes. Here we have shown that mutant male mice lacking ADAM1b are fertile and that the loss of ADAM1b results in no significant defect in sperm functions such as migration from the uterus into oviduct, binding to egg zona pellucida, and fusion with zona pellucida-free eggs. ADAM1b-deficient epididymal sperm showed a severe reduction of ADAM2 on the cell surface, despite the normal presence of ADAM2 in testicular germ cells. The appearance of ADAM1b and ADAM2 on the sperm surface depended on formation and abundance of ADAM1b/ADAM2 fertilin in testicular germ cells. These results suggest that mouse ADAM1b/ADAM2 fertilin may play a crucial role not in the sperm/ egg fusion but in the appearance of these two ADAMs on the sperm surface.

Mechanism of Fertilization: A Modern View

“…However, differing from expectation, the phenotype was not in sperm-egg fusion but rather impaired sperm-zona interaction [9]. Moreover, when fertilin-null spermatozoa were made by disrupting the Adam1b gene (ADAM1b being the second subunit of the fertilin heterodimer), the males remained fertile, despite the disappearance of fertilin [33]. The reason for the infertility in the Adam2-deficient/fertilin knockout mice was later discovered.…”

“…although the role of CD9 in fusion was suggested by the researchers in fertilization field [8], a tetraspanin protein CD9 was initially disrupted by the researchers in other fields to clarify its role in immunology, and was unexpectedly found to play an important role in spermegg fusion on eggs [32,33,39]. On the sperm side, a gene named Izumo1 emerged from analysis of an antigen reacting to monoclonal antibody OBF13 which inhibits sperm egg fusion.…”

The mechanism of sperm–egg interaction and the involvement of IZUMO1 in fusion

“…Therefore, the apparent phenotype of ADAM2 was not directly derived from the disappearance of fertilin from sperm, but from the impaired formation of testicular type fertilin. 19,20 Thus, the surprising outcome of gene disruption experiments is that fertilin is not essential for sperm-fertilizing ability despite considerable circumstantial evidence indicating that fertilin is the fusion protein.…”

“…19 Moreover, the removal of fertilin by disrupting Adam1b gene, the sperm can fertilize eggs without fertilin. 20 Why do these two different fertilin knockout mouse lines show a completely a different outcome? It is now understood that when the Adam2 gene was deleted, a testicular type of fertilin (ADAM1A/ADAM2) was disrupted together with fertilin (ADAM1B/ADAM2).…”

More Than a Simple Lock and Key Mechanism: Unraveling the Intricacies of Sperm-Zona Pellucida Binding

“…Angiotensin-converting enzyme (ACE) Mouse Rat Horse Human  Testis-specific form is found within developing spermatids and mature sperm  ACE KO mice are infertile due to defective transport in the oviducts as well as decreased zona pellucida binding  Play significant role in redistribution of ADAM3 to the sperm surface (Esther, et al, 1996, Foresta, et al, 1991, Kohn, et al, 1995, Langford, et al, 1993, Sibony, et al, 1993 A disintegrin and metalloproteinase (ADAMs) Mouse Rat Pig Human  Family of transmembrane proteins that have varying roles in maturation of spermatozoa  ADAM3 has important role in zona pellucida binding  ADAM2 KO mice show strong suppression of zona pellucida binding and difficulty in moving through female reproductive tract, due to absence of ADAM3 in these mice  ADAM1a KO mice are fertile, but show decreased levels of ADAM3 on the sperm surface  ADAM1b KO mice are fertile , Kim, et al, 2006a, Kim, et al, 2006b, Nishimura, et al, 2007, Yamaguchi, et al, 2009 protein that may facilitate sperm-zona pellucida binding by adhering to mannose-containing zona pellucida oligosaccharides (Cornwall, et al, 1991, Tulsiani, et al, 1993, Tulsiani, et al, 1989, Yoshida-Komiya, et al, 1999, , Hess, et al, 1996, Tantibhedhyangkul, et al, 2002, Weerachatyanukul, et al, 2003 Calmegin (CLGN)/Calnexin/Calspernin (CALR3)…”