Testicular and epididymal adams: expression and function during fertilization

ABSTRACT The disintegrin and metalloprotease domain-containing protein (ADAM) family of multidomain membrane proteins comprises at least 34 members in mammals. More than half of these

proteins are expressed specifically or predominantly in mammalian testes and epididymis, implying their prominence in male reproduction. These reproductive ADAMs can be classified into three

phylogenetic groups; designated I, II, and III. Each group displays remarkably contrasting features. Group I contains 11 ADAMs expressed in the testis. The genes that encode these proteins

lack introns in their coding sequences and most of the proteins are processed into prodomain-lacking forms in mature sperm. Five ADAMs—encoded by genes with multiple exons and introns—belong

to phylogenetic group II. These ADAMs are also expressed in testicular germ cells, but both prodomains and metalloprotease domains are lacking in mature sperm. Two phylogenetic group III

ADAMs are synthesized in the epididymis; one of which is secreted and transferred to the sperm surface. Some of these sperm ADAMs are assembled into potentially functional complexes,

including ADAM1B-ADAM2, ADAM2-ADAM3-ADAM4, ADAM2-ADAM3-ADAM5, and ADAM2-ADAM3-ADAM6. It has been suggested that ADAM2 and ADAM3 have roles in sperm–egg interactions. Mouse knockout studies

have revealed that the ADAM2-ADAM3 complex is critical for _in vivo_ sperm migratory function in the female reproductive tract. KEY POINTS * Male reproductive ADAMs are divided

phylogenetically into three major groups; group I (intronless testicular genes), group II (testicular genes with multiple exons and introns), and group III (epididymal genes) * Most of the

testicular ADAM proteins are synthesized in spermatogenic cells as precursors and processed to mature forms that are present on the surface of mature sperm * Some of the ADAMs that are

present in sperm form complexes, such as ADAM1B-ADAM2, ADAM2-ADAM3-ADAM4, ADAM2-ADAM3-ADAM5, and ADAM2-ADAM3-ADAM6 * Sperm ADAM complexes containing ADAM2 and ADAM3 are active during

sperm–egg interactions _in vitro_ and promote sperm migration from the uterus to the oviduct in mice * The ability to select sperm with optimal localization patterns and expression levels of

ADAMs or develop agonists that promote ADAM function could lead to improved IVF outcomes * Continuing studies of sperm ADAMs should provide important information regarding the molecular

mechanisms underlying mammalian fertilization Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access

through your institution Subscribe to this journal Receive 12 print issues and online access $209.00 per year only $17.42 per issue Learn more Buy this article * Purchase on SpringerLink *

Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional

subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE EXTRACELLULAR VESICLE TETRASPANIN CD63 JOURNEY FROM THE TESTIS THROUGH THE EPIDIDYMIS TO

MATURE BULL SPERM Article Open access 27 November 2024 ARRDC5 EXPRESSION IS CONSERVED IN MAMMALIAN TESTES AND REQUIRED FOR NORMAL SPERM MORPHOGENESIS Article Open access 17 April 2023 A

SMALL SECRETED PROTEIN NICOL REGULATES LUMICRINE-MEDIATED SPERM MATURATION AND MALE FERTILITY Article Open access 24 April 2023 ACCESSION CODES ACCESSIONS GENBANK/EMBL/DDBJ * NP_001007221 *

NP_001032811 * NP_001104248 * NP_001171071 * NP_003805 * NP_031425 * NP_031426 * NP_031427 * NP_031428 * NP_031429 * NP_031430 * NP_033745 * NP_033746 * NP_033748 * NP_033749 * NP_033750 *

NP_034212 * NP_034214 * NP_034215 * NP_034216 * NP_035911 * NP_065063 * NP_081941 * NP_291093 * NP_665688 * NP_700446 * NP_742124 * NP_777479 * NP_787953 REFERENCES * Cho, C. in _The ADAM

family of proteases_ (ed. Hooper, N. M. & Lendeckel, U.) 239–259 (Springer, Dordrecht, 2005). Book  Google Scholar  * Edwards, D. R., Handsley, M. M. & Pennington, C. J. The ADAM

metalloproteinases. _Mol. Aspects Med._ 29, 258–289 (2008). Article  CAS  PubMed  Google Scholar  * Primakoff, P. & Myls, D. G. The ADAM gene family: surface proteins with adhesion and

protease activity. _Trends Genet._ 16, 83–87 (2000). Article  CAS  PubMed  Google Scholar  * White, J. M. ADAMs: modulators of cell-cell and cell-matrix interactions. _Curr. Opin. Cell

Biol._ 15, 598–606 (2003). Article  CAS  PubMed  Google Scholar  * Seals, D. F. & Courtneidge, S. A. The ADAMs family of metalloproteases: multidomain proteins with multiple functions.

_Genes Dev._ 17, 7–30 (2003). Article  CAS  PubMed  Google Scholar  * Blobel, C. P. ADAMs: key components in EGFR signalling and development. _Nat. Rev. Mol. Cell Biol._ 6, 32–43 (2005).

Article  CAS  PubMed  Google Scholar  * Klein, T. & Bischoff, R. Active metalloproteases of the A Disintegrin and Metalloprotease (ADAM) family: biological function and structure. _J.

Proteome Res._ 10, 17–33 (2011). Article  CAS  PubMed  Google Scholar  * Poindexter, K., Nelson, N., DuBose, R. F., Black, R. A. & Cerretti, D. P. The identification of seven

metalloproteinase-disintegrin (ADAM) genes from genomic libraries. _Gene_ 237, 61–70 (1999). Article  CAS  PubMed  Google Scholar  * Choi, I. _ et al_. Characterization and comparative

genomic analysis of intronless Adams with testicular gene expression. _Genomics_ 83, 636–646 (2004). Article  CAS  PubMed  Google Scholar  * Yi, C. _ et al_. Expression analysis of the

Adam21 gene in mouse testis. _Gene Expr. Patterns_ 10, 152–158 (2010). Article  CAS  PubMed  Google Scholar  * Cho, C., Turner, L., Primakoff, P. & Myles, D. G. Genomic organization of

the mouse fertilin beta gene that encodes an ADAM family protein active in sperm-egg fusion. _Dev. Genet._ 20, 320–328 (1997). Article  CAS  PubMed  Google Scholar  * Choi, I. _ et al_.

Identification and characterization of ADAM32 with testis-predominant gene expression. _Gene_ 304, 151–162 (2003). Article  CAS  PubMed  Google Scholar  * Oh, J. _ et al_. Molecular,

biochemical, and cellular characterization of epididymal ADAMs, ADAM7 and ADAM28. _Biochem. Biophys. Res. Commun._ 331, 1374–1383 (2005). Article  CAS  PubMed  Google Scholar  * Cho, C.,

Primakoff, P., White, J. M. & Myles, D. G. Chromosomal assignment of four testis-expressed mouse genes from a new family of transmembrane proteins (ADAMs) involved in cell-cell adhesion

and fusion. _Genomics_ 34, 413–417 (1996). Article  CAS  PubMed  Google Scholar  * Nishimura, H. _ et al_. The ADAM1a and ADAM1b genes, instead of the ADAM1 (fertilin alpha) gene, are

localized on mouse chromosome 5. _Gene_ 291, 67–76 (2002). Article  CAS  PubMed  Google Scholar  * Bolcun, E., Rzymski, T., Nayernia, K. & Engel, W. ADAM family genes testase 2alpha and

2beta are chromosomally linked and simultaneously expressed in male germ cells. _Mol. Reprod. Dev._ 65, 19–22 (2003). Article  CAS  PubMed  Google Scholar  * Adham, I. M. _ et al_. Molecular

cloning, chromosomal localization, and expression analysis of CYRN1 and CYRN2, two human genes coding for cyritestin, a sperm protein involved in gamete interaction. _DNA Cell Biol._ 17,

161–168 (1998). Article  CAS  PubMed  Google Scholar  * Jury, J. A., Frayne, J. & Hall, L. The human fertilin alpha gene is non-functional: implications for its proposed role in

fertilization. _Biochem. J._ 321, 577–581 (1997). Article  CAS  PubMed  PubMed Central  Google Scholar  * Jury, J. A., Frayne, J. & Hall, L. Sequence analysis of a variety of primate

fertilin alpha genes: evidence for non-functional genes in the gorilla and man. _Mol. Reprod. Dev._ 51, 92–97 (1998). Article  CAS  PubMed  Google Scholar  * Waterston, R. H. _ et al_.

Initial sequencing and comparative analysis of the mouse genome. _Nature_ 420, 520–562 (2002). Article  CAS  PubMed  Google Scholar  * Frayne, J. & Hall, L. The gene for the human tMDC I

sperm surface protein is non-functional: implications for its proposed role in mammalian sperm-egg recognition. _Biochem. J._ 334, 171–176 (1998). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Grzmil, P. _ et al_. Human cyritestin genes (CYRN1 and CYRN2) are non-functional. _Biochem. J._ 357, 551–556 (2001). Article  CAS  PubMed  PubMed Central  Google Scholar  *

Blobel, C. P. _ et al_. A potential fusion peptide and an integrin ligand domain in a protein active in sperm-egg fusion. _Nature_ 356, 248–252 (1992). Article  CAS  PubMed  Google Scholar

  * Wolfsberg, T. G. _ et al_. The precursor region of a protein active in sperm-egg fusion contains a metalloprotease and a disintegrin domain: structural, functional, and evolutionary

implications. _Proc. Natl Acad. Sci. USA_ 90, 10783–10787 (1993). Article  CAS  PubMed  Google Scholar  * Perry, A. C., Gichuhi, P. M., Jones, R. & Hall, L. Cloning and analysis of

monkey fertilin reveals novel alpha subunit isoforms. _Biochem. J._ 307, 843–850 (1995). Article  CAS  PubMed  PubMed Central  Google Scholar  * Wolfsberg, T. G. _ et al_. ADAM, a widely

distributed and developmentally regulated gene family encoding membrane proteins with a disintegrin and metalloprotease domain. _Dev. Biol._ 169, 378–383 (1995). Article  CAS  PubMed  Google

Scholar  * Hardy, C. M. & Holland, M. K. Cloning and expression of recombinant rabbit fertilin. _Mol. Reprod. Dev._ 45, 107–116 (1996). Article  CAS  PubMed  Google Scholar  *

McLaughlin, E. A. _ et al_. Cloning and sequence analysis of rat fertilin alpha and beta—developmental expression, processing and immunolocalization. _Mol. Hum. Reprod._ 3, 801–809 (1997).

Article  CAS  PubMed  Google Scholar  * Waters, S. I. & White, J. M. Biochemical and molecular characterization of bovine fertilin alpha and beta (ADAM 1 and ADAM 2): a candidate

sperm-egg binding/fusion complex. _Biol. Reprod._ 56, 1245–1254 (1997). Article  CAS  PubMed  Google Scholar  * Frayne, J., Jury, J. A., Barker, H. L. & Hall, L. Rat MDC family of

proteins: sequence analysis, tissue distribution, and expression in prepubertal and adult rat testis. _Mol. Reprod. Dev._ 48, 159–167 (1997). Article  CAS  PubMed  Google Scholar  * Hooft

van Huijsduijnen, R. ADAM 20 and 21; two novel human testis-specific membrane metalloproteases with similarity to fertilin-alpha. _Gene_ 206, 273–282 (1998). Article  CAS  PubMed  Google

Scholar  * Cerretti, D. P., DuBose, R. F., Black, R. A. & Nelson, N. Isolation of two novel metalloproteinase-disintegrin (ADAM) cDNAs that show testis-specific gene expression.

_Biochem. Biophys. Res. Commun._ 263, 810–815 (1999). Article  CAS  PubMed  Google Scholar  * Brachvogel, B. _ et al_. Molecular cloning and expression analysis of a novel member of the

Disintegrin and Metalloprotease-Domain (ADAM) family. _Gene_ 288, 203–210 (2002). Article  CAS  PubMed  Google Scholar  * Zhu, G. Z., Lin, Y., Myles, D. G. & Primakoff, P. Identification

of four novel ADAMs with potential roles in spermatogenesis and fertilization. _Gene_ 234, 227–237 (1999). Article  CAS  PubMed  Google Scholar  * Liu, L. & Smith, J. W. Identification

of ADAM 31: a protein expressed in Leydig cells and specialized epithelia. _Endocrinology_ 141, 2033–2042 (2000). Article  CAS  PubMed  Google Scholar  * Day, A. E., Quilter, C. R., Sargent,

C. A. & Mileham, A. J. Chromosomal mapping, sequence and transcription analysis of the porcine fertilin beta gene (ADAM2). _Anim. Genet._ 34, 375–378 (2003). Article  CAS  PubMed 

Google Scholar  * Gupta, S. K., Alves, K., Palladino, L. O., Mark, G. E. & Hollis, G. F. Molecular cloning of the human fertilin beta subunit. _Biochem. Biophys. Res. Commun._ 224,

318–326 (1996). Article  CAS  PubMed  Google Scholar  * Vidaeus, C. M. _ et al_. Human fertilin beta: identification, characterization, and chromosomal mapping of an ADAM gene family member.

_Mol. Reprod. Dev._ 46, 363–369 (1997). Article  CAS  PubMed  Google Scholar  * Burkin, H. R., Burkin, D. J., Davey, P. M., Griffin, D. K. & Affara, N. A. Mapping, sequence, and

expression analysis of the human fertilin beta gene (FTNB). _Genomics_ 40, 190–192 (1997). Article  CAS  PubMed  Google Scholar  * Perry, A. C., Jones, R., Barker, P. J. & Hall, L. A

mammalian epididymal protein with remarkable sequence similarity to snake venom haemorrhagic peptides. _Biochem. J._ 286, 671–675 (1992). Article  CAS  PubMed  PubMed Central  Google Scholar

  * Cornwall, G. A. & Hsia, N. ADAM7, a member of the ADAM (a disintegrin and metalloprotease) gene family is specifically expressed in the mouse anterior pituitary and epididymis.

_Endocrinology_ 138, 4262–4272 (1997). Article  CAS  PubMed  Google Scholar  * Lin, Y. C., Sun, G. H., Lee, Y. M., Guo, Y. W. & Liu, H. W. Cloning and characterization of a complementary

DNA encoding a human epididymis-associated disintegrin and metalloprotease 7 protein. _Biol. Reprod._ 65, 944–950 (2001). Article  CAS  PubMed  Google Scholar  * Jury, J. A., Perry, A. C.

& Hall, L. Identification, sequence analysis and expression of transcripts encoding a putative metalloproteinase, eMDC II, in human and macaque epididymis. _Mol. Hum. Reprod._ 5,

1127–1134 (1999). Article  CAS  PubMed  Google Scholar  * Howard, L., Maciewicz, R. A. & Blobel, C. P. Cloning and characterization of ADAM28: evidence for autocatalytic pro-domain

removal and for cell surface localization of mature ADAM28. _Biochem. J._ 348, 21–27 (2000). Article  CAS  PubMed  PubMed Central  Google Scholar  * Haidl, I. D., Huber, G. & Eichmann,

K. An ADAM family member with expression in thymic epithelial cells and related tissues. _Gene_ 283, 163–170 (2002). Article  CAS  PubMed  Google Scholar  * Howard, L., Zheng, Y., Horrocks,

M., Maciewicz, R. A. & Blobel, C. Catalytic activity of ADAM28. _FEBS Lett._ 498, 82–86 (2001). Article  CAS  PubMed  Google Scholar  * Evans, J. P., Kopf, G. S. & Schultz, R. M.

Characterization of the binding of recombinant mouse sperm fertilin beta subunit to mouse eggs: evidence for adhesive activity via an egg beta1 integrin-mediated interaction. _Dev. Biol._

187, 79–93 (1997). Article  CAS  PubMed  Google Scholar  * Zhu, X., Bansal, N. P. & Evans, J. P. Identification of key functional amino acids of the mouse fertilin beta (ADAM2)

disintegrin loop for cell-cell adhesion during fertilization. _J. Biol. Chem._ 275, 7677–7683 (2000). Article  CAS  PubMed  Google Scholar  * Bigler, D. _ et al_. Sequence-specific

interaction between the disintegrin domain of mouse ADAM 2 (fertilin beta) and murine eggs. Role of the alpha(6) integrin subunit. _J. Biol. Chem._ 275, 11576–11584 (2000). Article  CAS 

PubMed  Google Scholar  * Takahashi, Y., Bigler, D., Ito, Y. & White, J. M. Sequence-specific interaction between the disintegrin domain of mouse ADAM 3 and murine eggs: role of beta1

integrin-associated proteins CD9, CD81, and CD98. _Mol. Biol. Cell_ 12, 809–820 (2001). Article  CAS  PubMed  PubMed Central  Google Scholar  * Tomczuk, M. _ et al_. Role of multiple beta1

integrins in cell adhesion to the disintegrin domains of ADAMs 2 and 3. _Exp. Cell Res._ 290, 68–81 (2003). Article  CAS  PubMed  Google Scholar  * Desiderio, U. V., Zhu, X. & Evans, J.

P. ADAM2 interactions with mouse eggs and cell lines expressing alpha4/alpha9 (ITGA4/ITGA9) integrins: implications for integrin-based adhesion and fertilization. _PLoS ONE_ 5, e13744

(2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Primakoff, P., Hyatt, H. & Tredick-Kline, J. Identification and purification of a sperm surface protein with a potential

role in sperm-egg membrane fusion. _J. Cell Biol._ 104, 141–149 (1987). Article  CAS  PubMed  Google Scholar  * Blobel, C. P., Myles, D. G., Primakoff, P. & White, J. M. Proteolytic

processing of a protein involved in sperm-egg fusion correlates with acquisition of fertilization competence. _J. Cell Biol._ 111, 69–78 (1990). Article  CAS  PubMed  Google Scholar  * Lum,

L. & Blobel, C. P. Evidence for distinct serine protease activities with a potential role in processing the sperm protein fertilin. _Dev. Biol._ 191, 131–145 (1997). Article  CAS  PubMed

  Google Scholar  * Phelps, B. M., Koppel, D. E., Primakoff, P. & Myles, D. G. Evidence that proteolysis of the surface is an initial step in the mechanism of formation of sperm cell

surface domains. _J. Cell Biol._ 111, 1839–1847 (1990). Article  CAS  PubMed  Google Scholar  * Hunnicutt, G. R., Koppel, D. E. & Myles, D. G. Analysis of the process of localization of

fertilin to the sperm posterior head plasma membrane domain during sperm maturation in the epididymis. _Dev. Biol._ 191, 146–159 (1997). Article  CAS  PubMed  Google Scholar  * Hunnicutt, G.

R., Koppel, D. E., Kwitny, S. & Cowan, A. E. Cyclic 3′, 5′-AMP causes ADAM1/ADAM2 to rapidly diffuse within the plasma membrane of guinea pig sperm. _Biol. Reprod._ 79, 999–1007 (2008).

Article  CAS  PubMed  PubMed Central  Google Scholar  * Frayne, J. _ et al_. Macaque MDC family of proteins: sequence analysis, tissue distribution and processing in the male reproductive

tract. _Mol. Hum. Reprod._ 4, 429–437 (1998). Article  CAS  PubMed  Google Scholar  * Cho, C., Ge, H., Branciforte, D., Primakoff, P. & Myles, D. G. Analysis of mouse fertilin in

wild-type and fertilin beta(-/-) sperm: evidence for C-terminal modification, alpha/beta dimerization, and lack of essential role of fertilin alpha in sperm-egg fusion. _Dev. Biol._ 222,

289–295 (2000). Article  CAS  PubMed  Google Scholar  * Kim, E., Nishimura, H. & Baba, T. Differential localization of ADAM1a and ADAM1b in the endoplasmic reticulum of testicular germ

cells and on the surface of epididymal sperm. _Biochem. Biophys. Res. Commun._ 304, 313–319 (2003). Article  CAS  PubMed  Google Scholar  * Kim, E. _ et al_. Processing and subcellular

localization of ADAM2 in the Macaca fascicularis testis and sperm. _Anim. Reprod. Sci._ 117, 155–159 (2010). Article  CAS  PubMed  Google Scholar  * Zhu, G. Z., Myles, D. G. & Primakoff,

P. Testase 1 (ADAM 24) a plasma membrane-anchored sperm protease implicated in sperm function during epididymal maturation or fertilization. _J. Cell. Sci._ 114, 1787–1794 (2001). CAS 

PubMed  Google Scholar  * Han, C. _ et al_. Comprehensive analysis of reproductive ADAMs: relationship of ADAM4 and ADAM6 with an ADAM complex required for fertilization in mice. _Biol.

Reprod._ 80, 1001–1008 (2009). Article  CAS  PubMed  Google Scholar  * Kim, E. _ et al_. Synthesis, processing, and subcellular localization of mouse ADAM3 during spermatogenesis and

epididymal sperm transport. _J. Reprod. Dev._ 50, 571–578 (2004). Article  CAS  PubMed  Google Scholar  * Kim, T. _ et al_. Expression and relationship of male reproductive ADAMs in mouse.

_Biol. Reprod._ 74, 744–750 (2006). Article  CAS  PubMed  Google Scholar  * Linder, B., Bammer, S. & Heinlein, U. A. Delayed translation and posttranslational processing of cyritestin,

an integral transmembrane protein of the mouse acrosome. _Exp. Cell Res._ 221, 66–72 (1995). Article  CAS  PubMed  Google Scholar  * Yuan, R., Primakoff, P. & Myles, D. G. A role for the

disintegrin domain of cyritestin, a sperm surface protein belonging to the ADAM family, in mouse sperm-egg plasma membrane adhesion and fusion. _J. Cell Biol._ 137, 105–112 (1997). Article

  CAS  PubMed  PubMed Central  Google Scholar  * Nishimura, H., Myles, D. G. & Primakoff, P. Identification of an ADAM2-ADAM3 complex on the surface of mouse testicular germ cells and

cauda epididymal sperm. _J. Biol. Chem._ 282, 17900–17907 (2007). Article  CAS  PubMed  Google Scholar  * Liu, H. W., Lin, Y. C., Chao, C. F., Chang, S. Y. & Sun, G. H. GP-83 and GP-39,

two glycoproteins secreted by human epididymis are conjugated to spermatozoa during maturation. _Mol. Hum. Reprod._ 6, 422–428 (2000). Article  CAS  PubMed  Google Scholar  * Sun, G. H.,

Lin, Y. C., Guo, Y. W., Chang, S. Y. & Liu, H. W. Purification of GP-83, a glycoprotein secreted by the human epididymis and conjugated to mature spermatozoa. _Mol. Hum. Reprod._ 6,

429–434 (2000). Article  CAS  PubMed  Google Scholar  * Oh, J. S., Han, C. & Cho, C. ADAM7 is associated with epididymosomes and integrated into sperm plasma membrane. _Mol. Cells_ 28,

441–446 (2009). Article  CAS  PubMed  Google Scholar  * Han, C. _ et al_. Identification of heat shock protein 5, calnexin and integral membrane protein 2B as Adam7-interacting membrane

proteins in mouse sperm. _J. Cell. Physiol._ 226, 1186–1195 (2011). Article  CAS  PubMed  Google Scholar  * Cho, C. _ et al_. Fertilization defects in sperm from mice lacking fertilin beta.

_Science_ 281, 1857–1859 (1998). Article  CAS  PubMed  Google Scholar  * Shamsadin, R. _ et al_. Male mice deficient for germ-cell cyritestin are infertile. _Biol. Reprod._ 61, 1445–1451

(1999). Article  CAS  PubMed  Google Scholar  * Nishimura, H., Cho, C., Branciforte, D. R., Myles, D. G. & Primakoff, P. Analysis of loss of adhesive function in sperm lacking cyritestin

or fertilin beta. _Dev. Biol._ 233, 204–213 (2001). Article  CAS  PubMed  Google Scholar  * Nishimura, H., Kim, E., Nakanishi, T. & Baba, T. Possible function of the ADAM1a/ADAM2

Fertilin complex in the appearance of ADAM3 on the sperm surface. _J. Biol. Chem._ 279, 34957–34962 (2004). Article  CAS  PubMed  Google Scholar  * Kim, E. _ et al_. Mouse sperm lacking

ADAM1b/ADAM2 fertilin can fuse with the egg plasma membrane and effect fertilization. _J. Biol. Chem._ 281, 5634–5639 (2006). Article  CAS  PubMed  Google Scholar  * Zhu, G. Z., Gupta, S.,

Myles, D. G. & Primakoff, P. Testase 1 (ADAM 24) a sperm surface metalloprotease is required for normal fertility in mice. _Mol. Reprod. Dev._ 76, 1106–1114 (2009). Article  CAS  PubMed

  Google Scholar  * Stein, K. K., Go, J. C., Primakoff, P. & Myles, D. G. Defects in secretory pathway trafficking during sperm development in Adam2 knockout mice. _Biol. Reprod._ 73,

1032–1038 (2005). Article  CAS  PubMed  Google Scholar  * Marcello, M. R., Jia, W., Leary, J. A., Moore, K. L. & Evans, J. P. Lack of tyrosylprotein sulfotransferase-2 activity results

in altered sperm-egg interactions and loss of ADAM3 and ADAM6 in epididymal sperm. _J. Biol. Chem._ 286, 13060–13070 (2011). Article  CAS  PubMed  PubMed Central  Google Scholar  * Suarez,

S. S. & Pacey, A. A. Sperm transport in the female reproductive tract. _Hum. Reprod. Update_ 12, 23–37 (2006). Article  CAS  PubMed  Google Scholar  * Yamaguchi, R. _ et al_. Disruption

of ADAM3 impairs the migration of sperm into oviduct in mouse. _Biol. Reprod._ 81, 142–146 (2009). Article  CAS  PubMed  Google Scholar  * Han, C. _ et al_. Impaired sperm aggregation in

Adam2 and Adam3 null mice. _Fertil. Steril._ 93, 2754–2756 (2010). Article  CAS  PubMed  Google Scholar  * Tokuhiro, K., Ikawa, M., Benham, A. M. & Okabe, M. Protein disulfide isomerase

homolog PDILT is required for quality control of sperm membrane protein ADAM3 and male infertility. _Proc. Natl Acad. Sci. USA_ 109, 3850–3855 (2012). Article  PubMed  Google Scholar  *

Monclus, M. A. _ et al_. Mouse sperm rosette: assembling during epididymal transit, _in vitro_ disassemble, and oligosaccharide participation in the linkage material. _Anat. Rec. (Hoboken)_

290, 814–824 (2007). Article  Google Scholar  * Yanagimachi, R. & Mahi, C. A. The sperm acrosome reaction and fertilization in the guinea-pig: a study _in vivo_. _J. Reprod. Fertil._ 46,

49–54 (1976). Article  CAS  PubMed  Google Scholar  * Moore, H., Dvorakova, K., Jenkins, N. & Breed, W. Exceptional sperm cooperation in the wood mouse. _Nature_ 418, 174–177 (2002).

Article  CAS  PubMed  Google Scholar  * Pizzari, T. & Foster, K. R. Sperm sociality: cooperation, altruism, and spite. _PLoS Biol._ 6, e130 (2008). Article  CAS  PubMed  PubMed Central 

Google Scholar  * Muga, A., Neugebauer, W., Hirama, T. & Surewicz, W. K. Membrane interaction and conformational properties of the putative fusion peptide of PH-30, a protein active in

sperm-egg fusion. _Biochemistry_ 33, 4444–4448 (1994). Article  CAS  PubMed  Google Scholar  * Niidome, T. _ et al_. Membrane interaction of synthetic peptides related to the putative

fusogenic region of PH-30 alpha, a protein in sperm-egg fusion. _J. Pept. Res._ 49, 563–569 (1997). Article  CAS  PubMed  Google Scholar  * Martin, I., Epand, R. M. & Ruysschaert, J. M.

Structural properties of the putative fusion peptide of fertilin, a protein active in sperm-egg fusion, upon interaction with the lipid bilayer. _Biochemistry_ 37, 17030–17039 (1998).

Article  CAS  PubMed  Google Scholar  * Wolfe, C. A. _ et al_. Membrane interactions of the putative fusion peptide (MF alpha P) from fertilin-alpha, the mouse sperm protein complex involved

in fertilization. _Mol. Membr. Biol._ 16, 257–263 (1999). Article  CAS  PubMed  Google Scholar  * Myles, D. G., Kimmel, L. H., Blobel, C. P., White, J. M. & Primakoff, P. Identification

of a binding site in the disintegrin domain of fertilin required for sperm-egg fusion. _Proc. Natl Acad. Sci. USA_ 91, 4195–4198 (1994). Article  CAS  PubMed  Google Scholar  * Almeida, E.

A. _ et al_. Mouse egg integrin alpha 6 beta 1 functions as a sperm receptor. _Cell_ 81, 1095–1104 (1995). Article  CAS  PubMed  Google Scholar  * Evans, J. P., Schultz, R. M. & Kopf, G.

S. Mouse sperm-egg plasma membrane interactions: analysis of roles of egg integrins and the mouse sperm homologue of PH-30 (fertilin) beta. _J. Cell. Sci._ 108, 3267–3278 (1995). CAS 

PubMed  Google Scholar  * Evans, J. P., Schultz, R. M. & Kopf, G. S. Roles of the disintegrin domains of mouse fertilins alpha and beta in fertilization. _Biol. Reprod._ 59, 145–152

(1998). Article  CAS  PubMed  Google Scholar  * Kim, E. _ et al_. Identification of a hyaluronidase, Hyal5, involved in penetration of mouse sperm through cumulus mass. _Proc. Natl Acad.

Sci. USA_ 102, 18028–18033 (2005). Article  CAS  PubMed  Google Scholar  * Hagaman, J. R. _ et al_. Angiotensin-converting enzyme and male fertility. _Proc. Natl Acad. Sci. USA_ 95,

2552–2557 (1998). Article  CAS  PubMed  Google Scholar  * Ikawa, M. _ et al_. The putative chaperone calmegin is required for sperm fertility. _Nature_ 387, 607–611 (1997). Article  CAS 

PubMed  Google Scholar  * Ikawa, M. _ et al_. Calsperin is a testis-specific chaperone required for sperm fertility. _J. Biol. Chem._ 286, 5639–5646 (2011). Article  CAS  PubMed  Google

Scholar  * Ikawa, M. _ et al_. Calmegin is required for fertilin alpha/beta heterodimerization and sperm fertility. _Dev. Biol._ 240, 254–261 (2001). Article  CAS  PubMed  Google Scholar  *

Yamaguchi, R., Yamagata, K., Ikawa, M., Moss, S. B. & Okabe, M. Aberrant distribution of ADAM3 in sperm from both angiotensin-converting enzyme (Ace)- and calmegin (Clgn)-deficient mice.

_Biol. Reprod._ 75, 760–766 (2006). Article  CAS  PubMed  Google Scholar  * Muro, Y. & Okabe, M. Mechanisms of fertilization—a view from the study of gene-manipulated mice. _J. Androl._

32, 218–225 (2011). Article  CAS  PubMed  Google Scholar  * Suarez, S. S. Regulation of sperm storage and movement in the mammalian oviduct. _Int. J. Dev. Biol._ 52, 455–462 (2008). Article

  PubMed  Google Scholar  * Ikawa, M., Inoue, N., Benham, A. M. & Okabe, M. Fertilization: a sperm's journey to and interaction with the oocyte. _J. Clin. Invest._ 120, 984–994

(2010). Article  CAS  PubMed  PubMed Central  Google Scholar  * Barraud-Lange, V. _ et al_. Cyclic QDE peptide increases fertilization rates and provides healthy pups in mouse. _Fertil.

Steril._ 91, 2110–2115 (2009). Article  CAS  PubMed  Google Scholar  * EMBL-EBI European Bioinformatics Institute. MUSCLE—Multiple Sequence Alignment [online], (2012). * Department of Genome

Sciences and the Department of Biology, University of Washington. PHYLIP [online], (2012). * National Center for Biotechnology Information. Gene [online], (2012). Download references

ACKNOWLEDGEMENTS The author thanks Boyeon Lee, Jun Tae Kwon, and Heejin Choi for help with manuscript preparation. This work was supported by Korea Science and Engineering Foundation Grant

2010-0028776, Korea Research Foundation Grant KRF-2008-313-C00736, and Gwangju Institute of Science and Technology Systems Biology Infrastructure Establishment Grant. AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS * School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 500-712, Korea Chunghee Cho Authors * Chunghee Cho View author publications You can

also search for this author inPubMed Google Scholar ETHICS DECLARATIONS COMPETING INTERESTS The author declares no competing financial interests. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Cho, C. Testicular and epididymal ADAMs: expression and function during fertilization. _Nat Rev Urol_ 9, 550–560 (2012).

https://doi.org/10.1038/nrurol.2012.167 Download citation * Published: 28 August 2012 * Issue Date: October 2012 * DOI: https://doi.org/10.1038/nrurol.2012.167 SHARE THIS ARTICLE Anyone you

share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the

Springer Nature SharedIt content-sharing initiative