SEPT14 complexes maintain sperm morphogenesis and function

The FASEB Journal, Год журнала: 2025, Номер 39(4)

Опубликована: Фев. 21, 2025

Abstract Mutations in the septin (SEPT) family lead to male infertility. Septin 14 (SEPT14) is abundantly expressed testis, and its expression significantly reduced individuals with teratozoospermia, suggesting that SEPT14 may play a role spermatogenesis. Here, we demonstrated Sept14 mainly at acroplaxome, manchette, neck, annulus during spermiogenesis. To study of sperm morphogenesis function, knockout ( −/− ) mice were generated. The subfertile presented phenotypes such as irregular acrosomes, DNA damage, disorganized mitochondria, displaced annuli. These abnormalities contributed motility impaired capacitation. Mechanistically, head, interacted colocalized microtubules actin manchette formation metamorphosis phase. In annulus, SEPT9, SEPT7, SEPT2 form filaments maintain localization annulus. GTP‐binding domain (GBD) GBD SEPT2, whereas C‐terminus SEPT7. Thus, our reveals mediating morphogenesis.

Язык: Английский

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KIF2C is essential for meiosis and manchette dynamics in male mice

Frontiers in Cell and Developmental Biology, Год журнала: 2025, Номер 13

Опубликована: Март 27, 2025

In gametogenesis, microtubules undergo dramatic changes known as microtubule dynamics, and which is important for fertility both male female. spermatogenesis, spindle dynamics occur during meiosis manchette in elongated spermatids. oogenesis, meiosis. The depolymerization protein kinesin-13 family (KIF2A, KIF2B, KIF2C) plays an role KIF2C a well-known factor mitosis. Although the function of mitosis has been extensively studied, its remains unclear. Additionally, formation We generated germ cell-specific Kif2c conditional knockout ( cKO) mice to elucidate cells. cKO showed chromosomal misalignment at meiotic metaphase, abnormal morphology delayed disassembly, led significant increase apoptosis. Furthermore, were completely infertile. Therefore, alignment contrast, female sufficiently fertile, only minor defects observed chromosome This study demonstrates, first time, that spermatogenesis achieve fertility, but not fertility.

Язык: Английский

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A novel amino-pyrimidine inhibitor suppresses tumor growth via microtubule destabilization and Bmi-1 down-regulation

Biochemical Pharmacology, Год журнала: 2025, Номер unknown, С. 116783 - 116783

Опубликована: Янв. 1, 2025

Язык: Английский

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Deficiency in DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice

Опубликована: Фев. 13, 2025

Asthenoteratozoospermia, a prevalent cause of male infertility, lacks well-defined etiology. DNAH12 is special dynein featured by the absence microtubule-binding domain, however, its functions in spermatogenesis remain largely unknown. Through comprehensive genetic analyses involving whole-exome sequencing and subsequent Sanger on infertile patients fertile controls from six distinct families, we unveiled biallelic mutations that co-segregate recessively with infertility studied families. Transmission electron microscopy (TEM) revealed pronounced axonemal abnormalities, including inner arms (IDAs) impairment central pair (CP) loss sperm flagella patients. Mouse models ( Dnah12 −/− mut/mut ) were generated recapitulated reproductive defects Noteworthy, deficiency did not show effects cilium organization function. Mechanistically, was confirmed to interact two other IDA components DNALI1 DNAH1, while disruption leads failed recruitment DNAH1 IDAs compromised development. Furthermore, also interacts radial spoke head proteins RSPH1, RSPH9, DNAJB13 regulate CP stability. Moreover, mice could be overcome intracytoplasmic injection (ICSI) treatment. Collectively, plays crucial role proper axoneme flagella, but cilia, recruiting both humans mice. These findings expand our comprehension component assembly cilia provide valuable marker for counseling diagnosis asthenoteratozoospermia clinical practice.

Язык: Английский

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Molecular insights into sperm head shaping and its role in human male fertility

Human Reproduction Update, Год журнала: 2025, Номер unknown

Опубликована: Март 3, 2025

Sperm head shaping, controlled by the acrosome-acroplaxome-manchette complex, represents a significant morphological change during spermiogenesis and involves numerous proteins expressed in spatially temporally specific manner. Defects sperm shaping frequently lead to teratozoospermia concomitant with oligozoospermia asthenozoospermia, but pathogenic mechanism underlying its role male infertility, remain poorly understood. This review aims summarize reveal relationship between gene defects associated infertility humans mice, explore potential clinical improvements ICSI treatment. We searched PubMed database for articles published English using keyword 'sperm shaping' combination following terms: 'acrosome formation', 'proacrosomal vesicles (PAVs)', 'manchette', 'perinuclear theca (PT)', 'chromatin condensation', 'linker of nucleoskeleton cytoskeleton (LINC) complex', 'histone-to-protamine (HTP) transition', 'male infertility', 'ICSI', 'artificial oocyte activation (AOA)'. The selected publications until 1 August 2024 were critically summarized, integrated, thoroughly discussed, irrelevant literature excluded. A total 6823 records retrieved. After careful screening, integrating relevant literature, excluding unrelated topic this review, 240 ultimately included analysis. Firstly, we reviewed important molecular events structures integral including PAV formation fusion, acrosome attachment nucleus, structure function manchette, PT, chromatin condensation, HTP transition. Then, set forth human identified genes related resulting asthenozoospermia. Finally, summarized outcomes cases from mutations as well through AOA infertile men impaired head. Understanding mechanisms holds profound implications, which may contribute risk prediction, genetic diagnosis, treatment infertility.

Язык: Английский

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Deficiency in DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice

eLife, Год журнала: 2025, Номер 13

Опубликована: Март 27, 2025

Asthenoteratozoospermia, a prevalent cause of male infertility, lacks well-defined etiology. DNAH12 is special dynein featured by the absence microtubule-binding domain, however, its functions in spermatogenesis remain largely unknown. Through comprehensive genetic analyses involving whole-exome sequencing and subsequent Sanger on infertile patients fertile controls from six distinct families, we unveiled biallelic mutations that co-segregate recessively with infertility studied families. Transmission electron microscopy (TEM) revealed pronounced axonemal abnormalities, including inner arms (IDAs) impairment central pair (CP) loss sperm flagella patients. Mouse models ( Dnah12 -/- mut/mut ) were generated recapitulated reproductive defects Noteworthy, deficiency did not show effects cilium organization function. Mechanistically, was confirmed to interact two other IDA components DNALI1 DNAH1, while disruption leads failed recruitment DNAH1 IDAs compromised development. Furthermore, also interacts radial spoke head proteins RSPH1, RSPH9, DNAJB13 regulate CP stability. Moreover, mice could be overcome intracytoplasmic injection (ICSI) treatment. Collectively, plays crucial role proper axoneme flagella, but cilia, recruiting both humans mice. These findings expand our comprehension component assembly cilia provide valuable marker for counseling diagnosis asthenoteratozoospermia clinical practice.

Язык: Английский

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Meiotic divisions and round spermatid formation do not require centriole duplication in mice

PLoS Genetics, Год журнала: 2025, Номер 21(4), С. e1011698 - e1011698

Опубликована: Апрель 28, 2025

Centrosomes, composed of centrioles and pericentriolar matrix proteins, are traditionally viewed as essential microtubule-organizing centers (MTOCs) that facilitate bipolar spindle formation chromosome segregation during spermatogenesis. In this study, we investigated the role in male germ cell development by using a murine conditional knockout (cKO) Sas4 , critical component centriole biogenesis. We found while duplication was impaired cKO spermatocytes, these cells were still capable progressing through meiosis I II. Chromosome able to proceed non-centrosomal MTOC, indicating not required for meiotic divisions. However, spermatids inherited fewer than two exhibited severe defects spermiogenesis, including improper manchette formation, constricted perinuclear rings, disrupted acrosome morphology, failure form flagella. Consequently, males infertile due absence functional spermatozoa. Our findings demonstrate dispensable cells, they spermiogenesis sperm maturation. This work provides key insights into centrosomes fertility may have implications understanding certain conditions infertility associated with defects.

Язык: Английский

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Function of manchette and intra-manchette transport in spermatogenesis and male fertility

Cell Communication and Signaling, Год журнала: 2025, Номер 23(1)

Опубликована: Май 29, 2025

The manchette is a transient skirt-like structure consisting of microtubules (MTs) and filamentous actin (F-actin) surrounding the elongating sperm head during spermiogenesis. It pivotal in shaping controlled by acrosome-acroplaxome-manchette complex, acrosome formation, flagellar assembly microtubular-based protein delivery. Defects frequently lead to teratozoospermia concomitant with oligozoospermia asthenozoospermia, but pathogenic mechanism underlying function its role male infertility remain poorly understood. In this review, we systematically described disassembly manchette, intra-manchette transport (IMT) regulatory model, IMT regulating spermatogenesis; summarized research progress manchette-related genes related infertility; listed proteins knockout mouse models clinical cases, which provide theoretical basis for an in-depth understanding molecular involved spermatogenesis fertility potentially developing treatments reproductive disorders.

Язык: Английский

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Contraceptive efficacy: Determining the threshold for effective suppression based on sperm concentration, motility, and morphology

Andrology, Год журнала: 2024, Номер 12(7), С. 1574 - 1584

Опубликована: Июль 19, 2024

Abstract Introdction Human spermatogenesis is a complex process that transforms spermatogonial stem cells through mitosis and meiosis to spermatozoa. Testosterone the key regulator of terminal stages meiosis, adherence spermatids Sertoli cells, spermiation. Follicle‐stimulating hormone (FSH) may be required for early important maintaining normal in men. Hormonal contraception suppresses FSH, luteinizing hormone, intratesticular testosterone concentration, resulting marked suppression sperm output. Results Clinical trials using alone or plus progestin demonstrate sustained concentration ≤1 million/mL sufficient prevent pregnancy female partner. New agents target could use this as contraceptive efficacy while others block function transport require lower threshold. When concentrations are suppressed such low levels, measurement motility morphology technically difficult unnecessary. With current data from fertile infertile men, it not possible establish limit percent equates prevention conception. compounds decrease alter need complete absence altered all spermatozoa ejaculate. Sperm tests useful depending on mechanism action each new compound. Conclusion Monitoring surrogate markers ensure effective relies laboratories experienced semen analyses. The development at‐home assess parameters has progressed rapidly. Some have been assessed clinical approved by regulatory agencies fertility assessment. However, caution must exercised these many rigorously validated against measured trained technologists standardized defined World Health Organization Semen Manual.

Язык: Английский

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Deficiency in a special dynein DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice

Опубликована: Авг. 27, 2024

Asthenoteratozoospermia, a prevalent cause of male infertility, lacks well-defined etiology. DNAH12 is special dynein featured by the absence microtubule-binding domain, however, its functions in spermatogenesis remain largely unknown. Through comprehensive genetic analyses involving whole-exome sequencing and subsequent Sanger on infertile patients fertile controls from six distinct families, we unveiled biallelic mutations that co-segregate recessively with infertility studied families. Transmission electron microscopy (TEM) revealed pronounced axonemal abnormalities, including inner arms (IDAs) impairment central pair (CP) loss sperm flagella patients. Mouse models ( Dnah12 −/− mut/mut ) were generated recapitulated reproductive defects Noteworthy, deficiency did not show effects cilium organization function. Mechanistically, was confirmed to interact two other IDA components DNALI1 DNAH1, while disruption leads failed recruitment DNAH1 IDAs compromised development. Furthermore, also interacts radial spoke head proteins RSPH1, RSPH9, DNAJB13 regulate CP stability. Moreover, mice could be overcome intracytoplasmic injection (ICSI) treatment. Collectively, plays crucial role proper axoneme flagella, but cilia, recruiting both humans mice. These findings expand our comprehension component assembly cilia provide valuable marker for counseling diagnosis asthenoteratozoospermia clinical practice.

Язык: Английский

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