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

Carvajal, Guillermo; Brukman, Nicolás G.; Muñoz, Mariana Weigel; Battistone, María Agustina; Guazzone, Vanesa Anabella; Ikawa, Masahito; Miyata, Haruhiko; Lustig, Livia; Breton, Sylvie; Cuasnicú, Patricia S.

doi:10.1038/s41598-018-35719-3

Cited by 32 publications

(55 citation statements)

References 89 publications

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“…Nine different sub-populations of principal cell were revealed, which were defined as c0.1-c0.8 (Figure 3A). The pan-principal cell marker Aqp9 (Carvajal et al, 2018; Pastor-Soler et al, 2001) was found in all 9 clusters (Figure 3C), as expected. The enriched genes in each of these 9 principal cell were listed in the supplementary Table S2.…”

Section: Resultssupporting

confidence: 82%

The landscape of mouse epididymal cells defined by the single-cell RNA-Seq

Shi

Sang

Xie

et al. 2020

Preprint

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Spermatozoa acquire their fertilizing ability and forward motility properties during epididymal transit. Although lots of attempts elucidating the functions of different cell types in epididymis, the composition of epididymal tubal and cell types are still largely unknown. Using single-cell RNA sequence, we analyzed the cell constitutions and their gene expression profiles of adult epididymis derived from caput, corpus and cauda epididymis with a total of 12,597 cells. This allowed us to elucidate the full range of gene expression changes during epididymis and derive region-specific gene expression signatures along the epididymis. A total of 7 cell populations were identified with all known constituent cells of mouse epididymis, as well as two novel cell types. Our analyses revealed a segment to segment variation of the same cell type in the three different part of epididymis and generated a reference dataset of epididymal cell gene expression. Focused analyses uncovered nine subtypes of principal cell. Two subtypes of principal cell, c0.3 and c.6 respectively, in our results supported with previous finding that they mainly located in the caput of mouse epididymis and play important roles during sperm maturation. We also showed unique gene expression signatures of each cell population and key pathways that may concert epididymal epithelial cell-sperm interactions. Overall, our single-cell RNA seq datasets of epididymis provide a comprehensive potential cell types and information-rich resource for the studies of epididymal composition, epididymal microenvironment regulation by the specific cell type, or contraceptive development, as well as a gene expression roadmap to be emulated in efforts to achieve sperm maturation regulation in the epididymis.

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Section: Resultssupporting

confidence: 82%

The landscape of mouse epididymal cells defined by the single-cell RNA-Seq

Shi

Sang

Xie

et al. 2020

Preprint

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“…). Our results revealed that, differently from single CRISP1 or CRISP4 KO mice, DKO males exhibited clear fertility defects (Carvajal et al ., ), confirming both the relevance of CRISP proteins for animal fertility and the existence of a functional compensation among CRISP family members. Moreover, the number of born pups correlated with the number of fertilized oviductal eggs in females mated by the same mutant males, indicating that DKO fertility defects were due to deficiencies in the in vivo fertilization process (Carvajal et al ., ).…”

Section: Crisp1/crisp4 Double Knockoutsupporting

confidence: 56%

“…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: 99%

“…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 ., ). As CRISP4 mutant spermatozoa did not exhibit defects in either cumulus penetration or sperm‐ZP binding, their lower fertilizing ability under the different conditions assayed would be mainly due to defects at ZP penetration and gamete fusion, likely associated to their impaired ability to undergo the acrosome reaction.…”

Section: Cysteine Rich Secretory Proteinmentioning

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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“…In humans, although the mechanisms underlying these processes still remain to be fully elucidated, there is one molecule that appears to be involved in suppressing sperm motility and capacitation through the inhibition of Catsper channels: CRISP1 [76], the first identified member of the highly evolutionarily conserved cysteine-rich secretory protein (CRISP) family. The role of CRISP1 in the male tract has been extensively studied, where upon its binding to spermatozoa in the epididymis, it is carried with these cells into the female tract, acting as a decapacitating factor [77][78][79][80][81]. In mice, CRISP1 inhibited membrane depolarization as well as Catsper signaling in epididymal spermatozoa, confirming the ability of the protein to block this sperm Ca 2+ channel [82].…”

Section: Discussionmentioning

confidence: 86%

Does the Pre-Ovulatory Pig Oviduct Rule Sperm Capacitation In Vivo Mediating Transcriptomics of Catsper Channels?

Martínez

Álvarez‐Rodríguez

Wright

et al. 2020

IJMS

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Spermatozoa need to conduct a series of biochemical changes termed capacitation in order to fertilize. In vivo, capacitation is sequentially achieved during sperm transport and interaction with the female genital tract, by mechanisms yet undisclosed in detail. However, when boar spermatozoa are stored in the tubal reservoir pre-ovulation, most appear to be in a non-capacitated state. This study aimed at deciphering the transcriptomics of capacitation-related genes in the pig pre-ovulatory oviduct, following the entry of semen or of sperm-free seminal plasma (SP). Ex-vivo samples of the utero-tubal junction (UTJ) and isthmus were examined with a microarray chip (GeneChip ® Porcine Gene 1.0 ST Array, Thermo Fisher Scientific) followed by bioinformatics for enriched analysis of functional categories (GO terms) and restrictive statistics. The results confirmed that entry of semen or of relative amounts of sperm-free SP modifies gene expression of these segments, pre-ovulation. It further shows that enriched genes are differentially associated with pathways relating to sperm motility, acrosome reaction, single fertilization, and the regulation of signal transduction GO terms. In particular, the pre-ovulation oviduct stimulates the Catsper channels for sperm Ca 2+ influx, with AKAPs, CATSPERs, and CABYR genes being positive regulators while PKIs and CRISP1 genes appear to be inhibitors of the process. We postulate that the stimulation of PKIs and CRISP1 genes in the pre-ovulation sperm reservoir/adjacent isthmus, mediated by SP, act to prevent premature massive capacitation prior to ovulation.

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

Cited by 32 publications

References 89 publications

The landscape of mouse epididymal cells defined by the single-cell RNA-Seq

The landscape of mouse epididymal cells defined by the single-cell RNA-Seq

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

Does the Pre-Ovulatory Pig Oviduct Rule Sperm Capacitation In Vivo Mediating Transcriptomics of Catsper Channels?

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