Epididymal cysteine-rich secretory proteins are required for epididymal sperm maturation and optimal sperm function

Hu, Jinghua; Merriner, D. Jo; O’Connor, Anne E; Houston, Brendan J; Furic, Luc; Hedger, Mark P.; O'Bryan, Moira K

doi:10.1093/molehr/gay001

Cited by 36 publications

(48 citation statements)

References 46 publications

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“…Differences in the genetic context and environmental conditions might also explain recent observations published during the preparation of this manuscript showing the absence of fertility and in vitro fertilization defects in DKO mice lacking CRISP1 and CRISP4 and exhibiting sperm functional defects (i.e. motility, AR, pTyr) and immune infiltrates in the epididymal stroma of old males 70 .…”

Section: Discussionmentioning

confidence: 84%

Impaired male fertility and abnormal epididymal epithelium differentiation in mice lacking CRISP1 and CRISP4

Carvajal

Brukman

Muñoz

et al. 2018

Sci Rep

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Epididymal Cysteine Rich Secretory Proteins 1 and 4 (CRISP1 and CRISP4) associate with sperm during maturation and play different roles in fertilization. However, males lacking each of these molecules individually are fertile, suggesting compensatory mechanisms between these homologous proteins. Based on this, in the present work, we generated double CRISP1/CRISP4 knockout (DKO) mice and examined their reproductive phenotype. Our data showed that the simultaneous lack of the two epididymal proteins results in clear fertility defects. Interestingly, whereas most of the animals exhibited specific sperm fertilizing ability defects supportive of the role of CRISP proteins in fertilization, one third of the males showed an unexpected epididymo-orchitis phenotype with altered levels of inflammatory molecules and non-viable sperm in the epididymis. Further analysis showed that DKO mice exhibited an immature epididymal epithelium and abnormal luminal pH, supporting these defects as likely responsible for the different phenotypes observed. These observations reveal that CRISP proteins are relevant for epididymal epithelium differentiation and male fertility, contributing to a better understanding of the fine-tuning mechanisms underlying sperm maturation and immunotolerance in the epididymis with clear implications for human epididymal physiology and pathology.

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Section: Discussionmentioning

confidence: 84%

Impaired male fertility and abnormal epididymal epithelium differentiation in mice lacking CRISP1 and CRISP4

Carvajal

Brukman

Muñoz

et al. 2018

Sci Rep

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“…Starting from the 1960s important sperm functions, such as the acquisition of sperm progressive motility and fertilizing capacity, were hypothesized under the control of the epididymis [ 56 , 57 ]. Considering that it is not surprising that epididymosomes convey to SPZ a large cargo of proteins encompassing key classes of enzymes, chaperones and structural proteins; for example, the cysteine-rich secretory protein 1 (CRISP1) regulates Ca 2+ channels in the sperm membrane [ 58 ], the sperm adhesion molecule 1 (SPAM1, also known as PH-20) is involved in sperm-zona pellucida adhesion [ 59 ] and the macrophage migration inhibitory factor (MIF) actively participates in sperm motility acquisition [ 60 ]. Epididymosomes also contain proteins providing antimicrobial and proteolytic attack protection [ 12 ], and glutathione peroxidase (GPX) enzymes preventing premature acrosome reaction and protecting sperm from oxidative stress [ 61 , 62 ].…”

Section: Exosomes In the Male Reproductive Tract: Their Potential mentioning

confidence: 99%

Exosome Composition and Seminal Plasma Proteome: A Promising Source of Biomarkers of Male Infertility

Candenas

Chianese

2020

IJMS

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Infertility has become a global health issue, with approximately 50% of infertility cases generated by disorders in male reproduction. Spermatozoa are conveyed towards female genital tracts in a safe surrounding provided by the seminal plasma. Interestingly, this dynamically changing medium is a rich source of proteins, essential not only for sperm transport, but also for its protection and maturation. Most of the seminal proteins are acquired by spermatozoa in transit through exosomes (epididymosomes and prostasomes). The high number of seminal proteins, the increasing knowledge of their origins and biological functions and their differential expression in the case of azoospermia, asthenozoospermia, oligozoospermia and teratozoospermia or other conditions of male infertility have allowed the identification of a wide variety of biomarker candidates and their involvement in biological pathways, thus to strongly suggest that the proteomic landscape of seminal plasma may be a potential indicator of sperm dysfunction. This review summarizes the current knowledge in seminal plasma proteomics and its potentiality as a diagnostic tool in different degrees of male infertility.

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“…The potential role of CRISP4 in fertilization and fertility was investigated by different groups using KO models (Gibbs et al ., ; Turunen et al ., ; Carvajal et al ., ; Hu et al ., ). Whereas males lacking CRISP4 were fertile in different genetic backgrounds (Gibbs et al ., ; Turunen et al ., ; Carvajal et al ., ; Hu et al ., ), several sperm capacitation‐associated parameters as well as the sperm fertilizing ability were differently affected in each strain (Turunen et al ., ; Carvajal et al ., ; Hu et al ., ). Spermatozoa from CRISP4 KO mice generated by our group failed to undergo protein tyrosine phosphorylation and the progesterone‐induced acrosome reaction during capacitation and were unable to fertilize cumulus‐invested, ZP‐intact and ZP‐free eggs (Carvajal et al ., ).…”

Section: Cysteine Rich Secretory Proteinmentioning

confidence: 97%

“…Results showed that CRISP1 mutant spermatozoa exhibited defects in capacitation‐associated parameters as well as in their ability to bind to the ZP and to fuse with the egg, confirming the roles of CRISP1 in sperm‐ZP binding and gamete fusion previously described (Rochwerger et al ., ; Cohen et al ., ; Busso et al ., ). However, in spite of the important roles of CRISP1 in fertilization, CRISP1 KO males were as fertile as controls (Da Ros et al ., ) even in mice from different genetic backgrounds (Hu et al ., ; Weigel Muñoz et al ., ). Considering the high sequence homology among CRISP family members, these observations support the existence of compensatory mechanisms between homologous CRISP.…”

Section: Cysteine Rich Secretory Proteinmentioning

confidence: 99%

“…Subsequent studies revealed that while group 1 males showed significantly lower fertility rates compared to controls, mice from group 2 exhibited severe fertility defects or were infertile when unilaterally or bilaterally affected, respectively (Carvajal et al ., ). These fertility defects were not found in recently reported DKO model for CRISP1 and CRISP4 (Hu et al ., ) very likely due to differences in the genetic context of the animals and/or environmental conditions.…”

Section: Crisp1/crisp4 Double Knockoutmentioning

confidence: 99%

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Relevance of CRISP proteins for epididymal physiology, fertilization, and fertility

et al. 2019

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Background: The molecular mechanisms involved in the acquisition of mammalian sperm fertilizing ability are still poorly understood, reflecting the complexity of this process. Objectives: In this review, we describe the role of Cysteine RIch Secretory Proteins (CRISP1-4) in different steps of the sperm journey to the egg as well as their relevance for fertilization and fertility. Materials and Methods: We analyze bibliography reporting the phenotypes of CRISP KO mice models and combine this search with recent findings from our team. Results: Generation of individual KO for CRISP proteins reveals they are key mediators in different stages of the fertilization process. However, in spite of their important functional roles, KO males for each of these proteins remain fertile, supporting the existence of compensatory mechanisms between homologous CRISP family members. The development of mice lacking epididymal CRISP1 and CRISP4 simultaneously (DKO) revealed that mutant males exhibit an impaired fertility due to deficiencies in the sperm ability to fertilize the eggs in vivo, consistent with the proposed roles of the two proteins in fertilization. Interestingly, DKO males show clear defects in both epididymal epithelium differentiation and luminal acidification known to be critical for sperm maturation and storage. Whereas in most of the cases, these epithelium defects seem to specifically affect the sperm fertilizing ability, some animals exhibit a disruption of the characteristic immune tolerance of the organ with clear signs of inflammation and sperm viability defects. Discussion and Conclusion: Altogether, these observations confirm the relevance of CRISP proteins for male fertility and contribute to a better understanding of the fine-tuning mechanisms underlying sperm maturation and immune tolerance within the epididymis. Moreover, considering the existence of a human epididymal protein functionally equivalent to rodent CRISP1 and CRISP4, DKO mice may represent an excellent model for studying human epididymal physiology and pathology.

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Epididymal cysteine-rich secretory proteins are required for epididymal sperm maturation and optimal sperm function

Abstract: This study was funded by the National Health and Medical Research Council, the Victorian Cancer Agency and a scholarship from the Chinese Scholarship Council. The authors have no conflicts of interest to declare.

Cited by 36 publications

References 46 publications

Impaired male fertility and abnormal epididymal epithelium differentiation in mice lacking CRISP1 and CRISP4

Impaired male fertility and abnormal epididymal epithelium differentiation in mice lacking CRISP1 and CRISP4

Exosome Composition and Seminal Plasma Proteome: A Promising Source of Biomarkers of Male Infertility

Relevance of CRISP proteins for epididymal physiology, fertilization, and fertility

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