A critical role of solute carrier 22a14 in sperm motility and male fertility in mice

Ca2+-dependent mechanisms are critical for successful completion of fertilization. Here, we demonstrate that CRISP1, a sperm protein involved in mammalian fertilization, is also present in the female gamete and capable of modulating key sperm Ca2+ channels. Specifically, we show that CRISP1 is expressed by the cumulus cells that surround the egg and that fertilization of cumulus–oocyte complexes from CRISP1 knockout females is impaired because of a failure of sperm to penetrate the cumulus. We provide evidence that CRISP1 stimulates sperm orientation by modulating sperm hyperactivation, a vigorous motility required for penetration of the egg vestments. Moreover, patch clamping of sperm revealed that CRISP1 has the ability to regulate CatSper, the principal sperm Ca2+ channel involved in hyperactivation and essential for fertility. Given the critical role of Ca2+ for sperm motility, we propose a novel CRISP1-mediated fine-tuning mechanism to regulate sperm hyperactivation and orientation for successful penetration of the cumulus during fertilization.

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Genetic Association of the Functional WDR4 Gene in Male Fertility

Journal of Personalized Medicine ◽

10.3390/jpm11080760 ◽

2021 ◽

Vol 11 (8) ◽

pp. 760

Author(s):

Yu-Jia Wang ◽

Eko Mugiyanto ◽

Yun-Ting Peng ◽

Wan-Chen Huang ◽

Wan-Hsuan Chou ◽

...

Keyword(s):

Male Infertility ◽

Genetic Association ◽

Sperm Motility ◽

Male Fertility ◽

Sperm Morphology ◽

Critical Role ◽

Clinical Manifestations ◽

Physiological Traits ◽

Clinical Records ◽

Low Expression

Infertility is one of the important problems in the modern world. Male infertility is characterized by several clinical manifestations, including low sperm production (oligozoospermia), reduced sperm motility (asthenozoospermia), and abnormal sperm morphology (teratozoospermia). WDR4, known as Wuho, controls fertility in Drosophila. However, it is unclear whether WDR4 is associated with clinical manifestations of male fertility in human. Here, we attempted to determine the physiological functions of WDR4 gene. Two cohorts were applied to address this question. The first cohort was the general population from Taiwan Biobank. Genomic profiles from 68,948 individuals and 87 common physiological traits were applied for phenome-wide association studies (PheWAS). The second cohort comprised patients with male infertility from Wan Fang Hospital, Taipei Medical University. In total, 81 male participants were recruited for the genetic association study. Clinical records including gender, age, total testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total sperm number, sperm motility, and sperm morphology were collected. In the first cohort, results from PheWAS exhibited no associations between WDR4 genetic variants and 87 common physiological traits. In the second cohort, a total of four tagging single-nucleotide polymorphisms (tSNPs) from WDR4 gene (rs2298666, rs465663, rs2248490, and rs3746939) were selected for genotyping. We found that SNP rs465663 solely associated with asthenozoospermia. Functional annotations through the GTEx portal revealed the correlation between TT or TC genotype and low expression of WDR4. Furthermore, we used mouse embryonic fibroblasts cells from mwdr4 heterozygous (+/‒) mice for functional validation by western blotting. Indeed, low expression of WDR4 contributed to ROS-induced DNA fragmentation. In conclusion, our results suggest a critical role of WDR4 gene variant as well as protein expression in asthenozoospermia.

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Targeted Ablation of Plasma Membrane Ca2+-ATPase (PMCA) 1 and 4 Indicates a Major Housekeeping Function for PMCA1 and a Critical Role in Hyperactivated Sperm Motility and Male Fertility for PMCA4

Journal of Biological Chemistry ◽

10.1074/jbc.m404628200 ◽

2004 ◽

Vol 279 (32) ◽

pp. 33742-33750 ◽

Cited By ~ 221

Author(s):

Gbolahan W. Okunade ◽

Marian L. Miller ◽

Gail J. Pyne ◽

Roy L. Sutliff ◽

Kyle T. O'Connor ◽

...

Keyword(s):

Plasma Membrane ◽

Sperm Motility ◽

Male Fertility ◽

Critical Role

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Dlec1 is required for spermatogenesis and male fertility in mice

Scientific Reports ◽

10.1038/s41598-020-75957-y ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yu Okitsu ◽

Mamoru Nagano ◽

Takahiro Yamagata ◽

Chizuru Ito ◽

Kiyotaka Toshimori ◽

...

Keyword(s):

Male Fertility ◽

Primary Cilia ◽

Critical Role ◽

Intraflagellar Transport ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Adenocarcinoma Cells ◽

Cilia Formation ◽

Ring Complex

Abstract Deleted in lung and esophageal cancer 1 (DLEC1) is a tumour suppressor gene that is downregulated in various cancers in humans; however, the physiological and molecular functions of DLEC1 are still unclear. This study investigated the critical role of Dlec1 in spermatogenesis and male fertility in mice. Dlec1 was significantly expressed in testes, with dominant expression in germ cells. We disrupted Dlec1 in mice and analysed its function in spermatogenesis and male fertility. Dlec1 deletion caused male infertility due to impaired spermatogenesis. Spermatogenesis progressed normally to step 8 spermatids in Dlec1−/− mice, but in elongating spermatids, we observed head deformation, a shortened tail, and abnormal manchette organization. These phenotypes were similar to those of various intraflagellar transport (IFT)-associated gene-deficient sperm. In addition, DLEC1 interacted with tailless complex polypeptide 1 ring complex (TRiC) and Bardet–Biedl Syndrome (BBS) protein complex subunits, as well as α- and β-tubulin. DLEC1 expression also enhanced primary cilia formation and cilia length in A549 lung adenocarcinoma cells. These findings suggest that DLEC1 is a possible regulator of IFT and plays an essential role in sperm head and tail formation in mice.

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Estrogen-Dependent and -Independent Estrogen Receptor-α Signaling Separately Regulate Male Fertility

Endocrinology ◽

10.1210/en.2008-1016 ◽

2009 ◽

Vol 150 (6) ◽

pp. 2898-2905 ◽

Cited By ~ 46

Author(s):

Kerstin W. Sinkevicius ◽

Muriel Laine ◽

Tamara L. Lotan ◽

Karolina Woloszyn ◽

John H. Richburg ◽

...

Keyword(s):

Estrogen Receptor ◽

Male Fertility ◽

Reproductive Tract ◽

Cell Function ◽

Critical Role ◽

Estrogen Receptor Α ◽

Male Reproductive Tract ◽

Efferent Ductule

Estrogen receptor-α (ERα) plays a critical role in male reproductive tract development and fertility. To determine whether estrogen-dependent and -independent ERα mechanisms are involved in male fertility, we examined male estrogen nonresponsive ERα knock-in mice. These animals have a point mutation (G525L) in the ligand-binding domain of ERα that significantly reduces interaction with, and response to, endogenous estrogens but does not affect growth factor activation of ligand-independent ERα pathways. Surprisingly, we found that ligand-independent ERα signaling is essential for concentrating epididymal sperm via regulation of efferent ductule fluid reabsorption. In contrast, estrogen-dependent ERα signaling is required for germ cell viability, most likely through support of Sertoli cell function. By treating estrogen nonresponsive ERα knock-in (ENERKI) mice with the ERα selective synthetic agonist propyl pyrazole triol, which is able to bind and activate G525L ERα in vivo, we discovered male fertility required neonatal estrogen-mediated ERα signaling. Thus, our work indicates both estrogen-dependent and -independent pathways play separable roles in male murine reproductive tract development and that the role of ERα in human infertility should be examined more closely.

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Zona Occludens-2 Is Critical for Blood–Testis Barrier Integrity and Male Fertility

Molecular Biology of the Cell ◽

10.1091/mbc.e08-12-1236 ◽

2009 ◽

Vol 20 (20) ◽

pp. 4268-4277 ◽

Cited By ~ 49

Author(s):

Jianliang Xu ◽

Farhana Anuar ◽

Safiah Mohamed Ali ◽

Mei Yong Ng ◽

Dominic C.Y. Phua ◽

...

Keyword(s):

Knockout Mice ◽

Male Fertility ◽

Connexin 43 ◽

Es Cells ◽

Critical Role ◽

Embryonic Stem ◽

Embryonic Lethality ◽

Barrier Integrity ◽

Blood Testis Barrier

Tight junction integral membrane proteins such as claudins and occludin are tethered to the actin cytoskeleton by adaptor proteins, notably the closely related zonula occludens (ZO) proteins ZO-1, ZO-2, and ZO-3. All three ZO proteins have recently been inactivated in mice. Although ZO-3 knockout mice lack an obvious phenotype, animals deficient in ZO-1 or ZO-2 show early embryonic lethality. Here, we rescue the embryonic lethality of ZO-2 knockout mice by injecting ZO-2(−/−) embryonic stem (ES) cells into wild-type blastocysts to generate viable ZO-2 chimera. ZO-2(−/−) ES cells contribute extensively to different tissues of the chimera, consistent with an extraembryonic requirement for ZO-2 rather than a critical role in epiblast development. Adult chimera present a set of phenotypes in different organs. In particular, male ZO-2 chimera show reduced fertility and pathological changes in the testis. Lanthanum tracer experiments show a compromised blood–testis barrier. Expression levels of ZO-1, ZO-3, claudin-11, and occludin are not apparently affected. ZO-1 and occludin still localize to the blood–testis barrier region, but claudin-11 is less well restricted and the localization of connexin-43 is perturbed. The critical role of ZO-2 for male fertility and blood–testis barrier integrity thus provides a first example for a nonredundant role of an individual ZO protein in adult mice.

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The Role of the SLP in Autism Spectrum Disorder Screening and Assessment

Perspectives on Language Learning and Education ◽

10.1044/lle15.2.50 ◽

2008 ◽

Vol 15 (2) ◽

pp. 50-59 ◽

Cited By ~ 1

Author(s):

Amy Philofsky

Keyword(s):

Language Development ◽

Critical Role ◽

Children With Autism ◽

Autism Spectrum ◽

Children With Asd ◽

Prevalence Estimates ◽

Notable Increase ◽

Screening Assessment ◽

Critical Components

AbstractRecent prevalence estimates for autism have been alarming as a function of the notable increase. Speech-language pathologists play a critical role in screening, assessment and intervention for children with autism. This article reviews signs that may be indicative of autism at different stages of language development, and discusses the importance of several psychometric properties—sensitivity and specificity—in utilizing screening measures for children with autism. Critical components of assessment for children with autism are reviewed. This article concludes with examples of intervention targets for children with ASD at various levels of language development.

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