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| Open AccessSTYXL1 regulates CCT complex assembly and flagellar tubulin folding in sperm formation
The sperm flagellum is composed of tubulin-based microtubules and is critical for sperm motility and thus male fertility. Here, the authors show that STYXL1 regulates CCT complex-facilitated tubulin folding and is essential for sperm flagella formation.
- Yu Chen
- , Mengjiao Luo
- & Xuejiang Guo
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Article
| Open AccessPhase-separated CCER1 coordinates the histone-to-protamine transition and male fertility
Here the authors reveal that phase‐separated nuclear CCER1 condensates are required for male fertility by mediating chromatin condensation and histone epigenetic modification, while loss‐of‐function variants of human CCER1 are pathogenic in patients with nonobstructive azoospermia (NOA).
- Dongdong Qin
- , Yayun Gu
- & Zhibin Hu
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Article
| Open AccessMaternal vitamin B1 is a determinant for the fate of primordial follicle formation in offspring
The authors show that maternal high-fat diet influences offspring’s ovarian reserve through maternal-embryonic cross-talk in mice and that maternal vitamin B1 supplementation could rescue ovarian primordial follicle reserve in mouse offspring.
- Wen-Xiang Liu
- , Hai-Ning Liu
- & Teng Zhang
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| Open AccessDeciphering a critical role of uterine epithelial SHP2 in parturition initiation at single cell resolution
The mechanism of parturition initiation remains elusive. Here, authors show that epithelium is an underestimated site for parturition initiation via epithelial PGF2a regulated by SHP2-COX1/COX2.
- Meng Liu
- , Mengjun Ji
- & Wenbo Deng
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| Open AccessA molecular staging model for accurately dating the endometrial biopsy
Natural variability in menstrual cycle length with rapid changes in gene expression makes it difficult to accurately compare different stages of the endometrial cycle. Here, the authors show a method for precisely determining endometrial cycle stage based on global gene expression that reveals remarkably synchronised daily changes for over 3,400 endometrial genes.
- W. T. Teh
- , J. Chung
- & P. A. W. Rogers
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| Open AccessDecoding the endometrial niche of Asherman’s Syndrome at single-cell resolution
Asherman’s Syndrome is characterized by intrauterine scarring and infertility. Here, the authors decode the Asherman’s Syndrome endometrial cell niche by single-cell RNA sequencing and in vitro analyses of patient-derived endometrial organoids.
- Xavier Santamaria
- , Beatriz Roson
- & Carlos Simon
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Article
| Open AccessControl of intracellular pH and bicarbonate by CO2 diffusion into human sperm
Bicarbonate (HCO3−) is critical in sperm for stimulation of cAMP synthesis during fertilization, though there is dispute over how HCO3− is transported into sperm. Here the authors use limit-of-detection LC/MS to characterize sperm protein expression and show that HCO3− is produced from CO2 diffusion into sperm rather than active transport.
- Elena Grahn
- , Svenja V. Kaufmann
- & U.Benjamin Kaupp
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| Open AccessSYPL1 defines a vesicular pathway essential for sperm cytoplasmic droplet formation and male fertility
The cytoplasmic droplet is an elusive structure of mammalian sperm. Here, the authors uncover a key gene that defines a vesicular pathway essential for cytoplasmic droplet formation and male fertility.
- Jiali Liu
- , Louis Hermo
- & Chen Chen
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Article
| Open AccessCFP1 governs uterine epigenetic landscapes to intervene in progesterone responses for uterine physiology and suppression of endometriosis
Progesterone (P4) signalling is involved in physiological control of the endometrium and contributes to the pathogenesis of endometrial diseases such as endometriosis. Here the authors report that CFP1, a regulator of histone methylation, controls endometrial responses to P4 and lack of endometrial CFP1 leads to failure of embryo implantation and exacerbated experimental endometriosis in mice.
- Seung Chel Yang
- , Mira Park
- & Haengseok Song
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Article
| Open AccessARRDC5 expression is conserved in mammalian testes and required for normal sperm morphogenesis
Male organisms produce huge numbers of sperm each day, with defects in the process resulting infertility. Here they show that arrestin domain-containing 5 (ARRDC5) is a testis-specific molecule required for mammalian spermatogenesis.
- Mariana I. Giassetti
- , Deqiang Miao
- & Jon M. Oatley
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Article
| Open AccessDiverse monogenic subforms of human spermatogenic failure
The GEMINI consortium sequenced 1,000 cases of idiopathic male infertility and identified a plausible Mendelian cause in 20% of cases. The infertility genes can be grouped by expression pattern, facilitating their interpretation and follow-up.
- Liina Nagirnaja
- , Alexandra M. Lopes
- & Donald F. Conrad
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Article
| Open AccessMicroencapsulation and nanowarming enables vitrification cryopreservation of mouse preantral follicles
Vitrification of preantral follicles is a promising strategy for female fertility preservation, but requires high concentrations of toxic cryoprotectants. Here, the authors accomplish follicle vitrification with low cryoprotectants by taking advantage of microencapsulation and nanowarming.
- Conghui Tian
- , Lingxiao Shen
- & Gang Zhao
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Article
| Open AccessDefinition of the estrogen negative feedback pathway controlling the GnRH pulse generator in female mice
Estrogen secreted by the ovary controls how the brain drives pulsatile reproductive hormone secretion. The authors show that in mice, estrogen receptor alpha within a specific population of hypothalamic kisspeptin neurons is the principal pathway through which estrogen brings about this classic negative feedback pathway common to all mammals.
- H. James McQuillan
- , Jenny Clarkson
- & Allan E. Herbison
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Article
| Open AccessTargeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models
Type 2 diabetes often presents with reproductive disorders, including reduced male and female fertility. Here they show that diabetes disrupts the APLN signaling axis in the testes and that spermatogenesis can be restored through treatment with an APLN antagonist.
- Ke Song
- , Xinyan Yang
- & Xiao-Yang Zhao
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Article
| Open AccessBNC1 deficiency-triggered ferroptosis through the NF2-YAP pathway induces primary ovarian insufficiency
Primary ovarian insufficiency (POI) is a clinical syndrome of ovarian dysfunction that results in infertility. Here they show that BCN1 mutation results in premature ovarian follicle activation and atresia through dysregulation of ferroptosis.
- Feixia Wang
- , Yifeng Liu
- & Dan Zhang
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Article
| Open AccesshnRNPH1 recruits PTBP2 and SRSF3 to modulate alternative splicing in germ cells
Coordinated regulation of alternative splicing is essential for germ cell development. Here, the authors report that hnRNPH1 interacts with alternative splicing factors PTBP2 and SRSF3 in the germline to regulate pre-mRNA alternative splicing.
- Shenglei Feng
- , Jinmei Li
- & Shuiqiao Yuan
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Article
| Open AccessDynamic mRNA degradome analyses indicate a role of histone H3K4 trimethylation in association with meiosis-coupled mRNA decay in oocyte aging
Developmental potential of oocytes decreases in women of advanced age. Here the authors observe impaired meiosis-coupled mRNA decay and reduced CXXC1-maintained histone H3K4 trimethylation in old oocytes of mouse and humans.
- Yun-Wen Wu
- , Sen Li
- & Qian-Qian Sha
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Article
| Open AccessLoss of MIG-6 results in endometrial progesterone resistance via ERBB2
Female subfertility is highly associated with endometriosis. Here the authors show that progesterone-induced MIG-6 is reduced in endometrium of infertile women and non-human primates with endometriosis, and in a mouse model find that Erbb2 is the key mediator of Mig-6 loss induced endometriosis-related infertility.
- Jung-Yoon Yoo
- , Tae Hoon Kim
- & Jae-Wook Jeong
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Article
| Open AccessMenin directs regionalized decidual transformation through epigenetically setting PTX3 to balance FGF and BMP signaling
The decidualization of endometrial stroma is critical for pregnancy maintenance. Here the authors reveal that Menin ensures the expression of PTX3 through H3K4me3 modification, to balance the BMP and FGF signal in the decidua for normal pregnancy.
- Mengying Liu
- , Wenbo Deng
- & Shuangbo Kong
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Article
| Open AccessTrkB agonist antibody ameliorates fertility deficits in aged and cyclophosphamide-induced premature ovarian failure model mice
Qin et al. report that an agonistic antibody targeting the BDNF receptor TrkB promotes follicle development and oocyte maturation, and reverse ovarian deficits and infertility in aged and cyclophosphamide-induced premature ovarian failure model mice.
- Xunsi Qin
- , Yue Zhao
- & Bai Lu
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| Open AccessA de novo paradigm for male infertility
Germline de novo mutations can impact individual fitness, but their role in human male infertility is understudied. Trio-based exome sequencing identifies many new candidate genes affecting male fertility, including an essential regulator of male germ cell pre-mRNA splicing.
- M. S. Oud
- , R. M. Smits
- & J. A. Veltman
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| Open AccessCell-fate transition and determination analysis of mouse male germ cells throughout development
The full-term developmental profile of male germ cells remains undefined. Here, the authors use single-cell sequencing to investigate the transcriptome landscapes of mouse male germ cells throughout development and find several critical regulators for prenatal cell-fate determination.
- Jiexiang Zhao
- , Ping Lu
- & Xiao-Yang Zhao
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| Open AccessAging, inflammation and DNA damage in the somatic testicular niche with idiopathic germ cell aplasia
Molecular mechanisms associated with human germ cell aplasia in infertile men remain undefined. Here the authors perform single-cell transcriptome profiling to highlight differentially expressed genes and pathways in each somatic cell type in testes of men with idiopathic germ cell aplasia.
- Massimo Alfano
- , Anna Sofia Tascini
- & Andrea Salonia
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Article
| Open AccessThe missing linker between SUN5 and PMFBP1 in sperm head-tail coupling apparatus
The sperm head-to-tail coupling apparatus ensures sperm head-tail integrity, but mechanistic insights remain limited. Here the authors demonstrate that CENTLEIN links and controls the interaction between SUN5 and PMFBP1, indicating that its impairments might be associated with acephalic spermatozoa syndrome.
- Ying Zhang
- , Chao Liu
- & Li Yuan
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Article
| Open AccessThe genetic architecture of sporadic and multiple consecutive miscarriage
Miscarriage affects around 15% of clinically confirmed pregnancies. Here the authors carry out a large genome-wide association study for sporadic and multiple consecutive miscarriage and suggest links with placental biology.
- Triin Laisk
- , Ana Luiza G. Soares
- & Cecilia M. Lindgren
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| Open AccessSingle-cell analysis of developing and azoospermia human testicles reveals central role of Sertoli cells
Non-obstructive azoospermia affects 1% of men. Here, authors perform single-cell transcriptomic analysis of human testicular cells from healthy donors and non-obstructive azoospermia patients and find that inhibition of Wnt signaling promotes the maturation of Sertoli cells from patients.
- LiangYu Zhao
- , ChenCheng Yao
- & Zheng Li
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Article
| Open AccessUHRF1 suppresses retrotransposons and cooperates with PRMT5 and PIWI proteins in male germ cells
Retrotransposons are silenced by an epigenetic mechanism and piRNA pathway in the mammalian germline. Here, the authors report that UHRF1 suppresses retrotransposons by interacting with PRMT5 and PIWI proteins during spermatogenesis.
- Juan Dong
- , Xiaoli Wang
- & Shuiqiao Yuan
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Article
| Open AccessRare mutations in the complement regulatory gene CSMD1 are associated with male and female infertility
Many molecular and physiological mechanisms in the regulation of fertility are shared between female and male mammals. Here, Lee et al. report an association of CNVs in CSMD1 with early idiopathic menopause in women and show that loss of Csmd1 leads to gonadal dysfunction in both male and female mice.
- Arthur S. Lee
- , Jannette Rusch
- & Donald F. Conrad
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Article
| Open AccessMolecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility
Glycoprotein ZP1 is a component of the oocyte’s zona pellucida (ZP), and mutations in human ZP1 are linked to female infertility. Here, using structure-function analysis, the authors suggest that filament cross-linking by ZP1 is required to form a stable ZP in human, and infertility mutations interfere with cross-linking.
- Kaoru Nishimura
- , Elisa Dioguardi
- & Luca Jovine
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| Open AccessMutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human
Asthenozoospermia is a major cause of male infertility, and multiple morphological abnormalities of the flagella (MMAF) is a particularly severe form. Here, using whole-exome sequencing of 78 MMAF patients, the authors identify mutations in two WDR proteins, CFAP43 and CFAP44, and confirm that these proteins are required for flagellogenesis in mouse and Trypanosoma brucei.
- Charles Coutton
- , Alexandra S. Vargas
- & Pierre F. Ray
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| Open AccessTridimensional visualization reveals direct communication between the embryo and glands critical for implantation
Embryo implantation initiates the interaction of the blastocyst with the uterus and occurs within a specialised crypt formed by uterine epithelial cells. Here, using 3D imaging techniques of wild type and mutant uteri, the authors show that crypt formation occurs with preexisting glands of the uterus, opening communication between glands and the implanting embryo.
- Jia Yuan
- , Wenbo Deng
- & Sudhansu. K. Dey
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Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men
Differential selection on sex-specific genes facilitates propagation of deleterious mutations. Here, the authors show that genes exclusively expressed in human testes harbour a greater number of deleterious mutations than genes expressed in both sexes, due to reduced selection in females.
- Moran Gershoni
- & Shmuel Pietrokovski
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Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men
Non-obstructive azoospermia (NOA) is a major cause of male infertility. Here, the authors provide insight into the genetic basis of NOA by identifying three new genetic risk loci in a genome-wide association study and reporting a fourth potential NOA susceptibility locus based on a Drosophilaknockdown experiment.
- Zhibin Hu
- , Zheng Li
- & Jiahao Sha
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Dependence of fertility on kisspeptin–Gpr54 signaling at the GnRH neuron
The kisspeptin receptor GPR54 is implicated in the maintenance of mammalian fertility. Kirilov et al.study GPR54 mutant mice and identify a subset of neurons in the brain expressing gonadotropin-releasing hormone as the critical site for kisspeptin action.
- Milen Kirilov
- , Jenny Clarkson
- & Allan E. Herbison