The Small Heat Shock Protein ODF1/HSPB10 Is Essential for Tight Linkage of Sperm Head to Tail and Male Fertility in Mice

Yang, Kefei; Meinhardt, Andreas; Zhang, Bing; Grzmil, Paweł; Adham, Ibrahim M.; Hoyer‐Fender, Sigrid

doi:10.1128/mcb.06158-11

Cited by 131 publications

(127 citation statements)

References 63 publications

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“…A second group of Taf7l-regulated genes [Odf1, testis-specific serine kinase 6 (Tssk6), sperm motility kinase 2a/b (Smok2a/b), and Smok3a/b] have been implicated in sperm structure and motility during late stages of spermatogenesis ( Fig. 2 B and C) (27)(28)(29)(30). Additionally, a group of genes that have generally been classified as ones involved in metabolism are significantly down-regulated in the testis upon loss of Taf7l and likely reflect both metabolic and spermatogenesis functions.…”

Section: Resultsmentioning

confidence: 99%

Taf7l cooperates with Trf2 to regulate spermiogenesis

Zhou

Grubisic

Zheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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TATA-binding protein (TBP)-associated factor 7l (Taf7l; a paralogue of Taf7) and TBP-related factor 2 (Trf2) are components of the core promoter complex required for gene/tissue-specific transcription of protein-coding genes by RNA polymerase II. Previous studies reported that Taf7l knockout (KO) mice exhibit structurally abnormal sperm, reduced sperm count, weakened motility, and compromised fertility. Here we find that continued backcrossing of Taf7l −/Y mice from N5 to N9 produced KO males that are essentially sterile. Genome-wide expression profiling by mRNA-sequencing analysis of wild-type (WT) and Taf7l −/Y (KO) testes revealed that Taf7l ablation impairs the expression of many postmeiotic spermatogenic-specific as well as metabolic genes. Importantly, histological analysis of testes revealed that Taf7l −/Y mice develop postmeiotic arrest at the first stage of spermiogenesis, phenotypically similar to Trf2 −/− mice, but distinct from Taf4b −/− mice. Indeed, we find that Taf7l and Trf2 coregulate postmeiotic genes, but none of Taf4b-regulated germ stem cell genes in testes. Genome-wide ChIP-sequencing studies indicate that TAF7L binds to promoters of activated postmeiotic genes in testis. Moreover, biochemical studies show that TAF7L associates with TRF2 both in vitro and in testis, suggesting that TAF7L likely cooperates directly with TRF2 at promoters of a subset of postmeiotic genes to regulate spermiogenesis. Our findings thus provide a previously undescribed mechanism for cell-type-specific transcriptional control involving an interaction between a "nonprototypic" core promoter recognition factor (Trf2) and an orphan TAF subunit (Taf7l) in mammalian testis-specific gene transcription.gene regulation | reproduction | RNA-seq | contraceptive medicine S permatogenesis is a cyclic process in which diploid spermatogonia differentiate into mature haploid spermatozoa. This process is mainly driven by two-pre-and postmeiotictranscription waves that are tightly controlled by testis-specific transcription factors. During the premeiotic transcription phase, individual spermatogonia are committed to differentiating into primary spermatocytes that later undergo two meiotic divisions to generate haploid round spermatids connected by intercellular cytoplasmic bridges (1-3). During the postmeiotic transcription phase of spermiogenesis, haploid round spermatids are sculptured into the elongated shape of mature spermatozoa. These latter stages are accompanied by dramatic biochemical and morphological changes, including major remodeling of chromatin with protamines substituting for somatic histones to tightly pack DNA into the sperm nucleus.Understanding the intricate mechanisms that control spermatogenesis has important implications for human health and reproduction. A key step in the regulation of spermatogenesis occurs at the level of transcription, starting with the use of distinct promoter elements (4) within uniquely reorganized chromatin (5) and driven by the action of several testis-specific transcription factors...

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Section: Resultsmentioning

confidence: 99%

Taf7l cooperates with Trf2 to regulate spermiogenesis

Zhou

Grubisic

Zheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Similarly, mice lacking Odf1 or Oaz3 also display acephalic spermatozoa with partial penetrance (21,22). Partial penetrance observed in both humans and animals (5-19, 47, 48) suggests that this condition is variable and can be caused by either a partial loss of function of Spata6 or mutations in other genes involved in SPATA6-mediated segmented column formation during spermiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Mice lacking Odf1, a gene encoding outer dense fiber protein 1, display fragile sperm connecting pieces in addition to a disorganized mitochondrial sheath and defective outer dense fibers (ODFs) (21). Inactivation of Oaz3, a gene encoding ornithine decarboxylase antizyme 3, also leads to fragile sperm connecting pieces, despite the observation that all major structures of the connecting piece appear to be intact in mice (22).…”

mentioning

confidence: 99%

Spata6is required for normal assembly of the sperm connecting piece and tight head–tail conjunction

Yuan

Stratton

Bao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

139

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"Pinhead sperm," or "acephalic sperm," a type of human teratozoospermia, refers to the condition in which ejaculate contains mostly sperm flagella without heads. Family clustering and homogeneity of this syndrome suggests a genetic basis, but the causative genes remain largely unknown. Here we report that Spata6, an evolutionarily conserved testis-specific gene, encodes a protein required for formation of the segmented columns and the capitulum, two major structures of the sperm connecting piece essential for linking the developing flagellum to the head during late spermiogenesis. Inactivation of Spata6 in mice leads to acephalic spermatozoa and male sterility. Our proteomic analyses reveal that SPATA6 is involved in myosin-based microfilament transport through interaction with myosin subunits (e.g., MYL6).M ale gametes-spermatozoa-are produced in the testis through a process termed spermatogenesis, which can be divided into three phases: mitotic, meiotic, and haploid (1). In the mitotic phase, spermatogonial stem cells proliferate and differentiate into spermatogonia, which subsequently enter the meiotic phase and become spermatocytes. Spermatocytes undergo crossover, followed by two consecutive meiotic cell divisions to produce haploid spermatids. Spermatids then undergo a multistep differentiation process, also called spermiogenesis, to form spermatozoa. Severe disruptions in either the mitotic or the meiotic phase tend to cause azoospermia, whereas spermiogenic defects often lead to reduced sperm counts, aberrant sperm motility, and deformed spermatozoa, a condition termed oligoasthenoteratozoospermia (OAT) in humans (2, 3).OAT accounts for a significant proportion of male idiopathic infertility cases (2, 4). Numerous cases of acephalic spermatozoa have been reported in teratozoospermic patients (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). In these patients, the major anomaly lies in headless spermatozoa in the ejaculate, and the headless spermatozoa were initially called "pinhead sperm" because the investigators mistakenly regarded the retained cytoplasmic droplets, which are usually attached to the midprincipal piece junction of the flagella, as the heads of reduced size (8,13,14). Extensive ultrastructral studies on humans and animals with acephalic spermatozoa suggest that this condition results from defects in formation of the connecting piece of spermatozoa during late spermiogenesis, including failure for the proximal centrioles to attach normally to the caudal portion of the sperm nuclei, leading to abnormal head-midpiece alignment, or a nuclear defect that interferes with formation of the implantation fossa, the normal lodging site for the sperm proximal centriole (16). Aberrant formation of the connecting piece leads to independent development of the sperm heads and flagella, and eventually these structures become separated within the seminiferous tubules or during their transition through the seminal tract as a consequence of increased instability of the head-midpiece junction (16,18)....

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“…We have recently demonstrated that ODF1 is essential for male fertility in mice. By deletion of the single copy Odf1 gene in mice, we could show that complete ablation of ODF1 on mixed genetic background resulted in acephalic sperm, whereas heterozygosity affected only sperm motility (Hoyer-Fender et al 1995, Yang et al 2012. Therefore, ODF1 has been figured out as an essential component of the sperm head-to-tail linkage apparatus.…”

Section: Introductionmentioning

confidence: 99%

Haplo-deficiency of ODF1/HSPB10 in mouse sperm causes relaxation of head-to-tail linkage

Yang¹,

Grzmil²,

Meinhardt³

et al. 2014

Reproduction

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The small heat shock protein ODF1/HSPB10 is essential for male fertility in mice. Targeted deletion of Odf1 resulted in acephalic sperm in homozygous mice of mixed background (C57BL/6J//129/Sv), whereas heterozygous animals are fully fertile. To further elucidate the function of ODF1, we generated incipient congenic mice with targeted deletion of Odf1 by successive backcrossing on the 129/Sv background. We observed that fecundity of heterozygous Odf1 C/K male mice was severely reduced over backcross generations. However, neither aberrant sperm parameters nor sperm anomalies could be observed. Ultra-structural analyses of sperm from incipient congenic heterozygous Odf1 C/K males of backcross generation N7 revealed no obvious pathological findings. However, we observed an enlargement of the distance between nuclear membrane and capitulum, indicating a weakening of the sperm head-to-tail coupling. Severe male subfertility provoked by haplo-deficiency of ODF1 is therefore most probably caused by impaired head-to-tail coupling that eventually might induce sperm decapitation on the specific conditions of in vivo fertilisation. As subfertility in haplo-deficient ODF1 male mice could not be diagnosed by semen analysis, it seems to be a paradigm for unexplained infertility that is a frequent diagnosis for male fertility impairment in humans.

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The Small Heat Shock Protein ODF1/HSPB10 Is Essential for Tight Linkage of Sperm Head to Tail and Male Fertility in Mice

Cited by 131 publications

References 63 publications

Taf7l cooperates with Trf2 to regulate spermiogenesis

Taf7l cooperates with Trf2 to regulate spermiogenesis

Spata6is required for normal assembly of the sperm connecting piece and tight head–tail conjunction

Haplo-deficiency of ODF1/HSPB10 in mouse sperm causes relaxation of head-to-tail linkage

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