Essential role for SUN5 in anchoring sperm head to the tail

SUN (Sad1 and UNC84 domain containing)-domain proteins are reported to reside on the nuclear membrane playing distinct roles in nuclear dynamics. SUN5 is a new member of the SUN family, with little knowledge regarding its function. Here, we generated Sun5−/− mice and found that male mice were infertile. Most Sun5-null spermatozoa displayed a globozoospermia-like phenotype but they were actually acephalic spermatozoa. Additional studies revealed that SUN5 was located in the neck of the spermatozoa, anchoring sperm head to the tail, and without functional SUN5 the sperm head to tail coupling apparatus was detached from nucleus during spermatid elongation. Finally, we found that healthy heterozygous offspring could be obtained via intracytoplasmic injection of Sun5-mutated sperm heads for both male mice and patients. Our studies reveal the essential role of SUN5 in anchoring sperm head to the tail and provide a promising way to treat this kind of acephalic spermatozoa-associated male infertility.

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Ccdc38 is required for sperm flagellum biogenesis and male fertility in mouse

10.1101/2022.01.10.475757 ◽

2022 ◽

Author(s):

Ruidan Zhang ◽

Wei Li ◽

Li Yuan ◽

Fei Gao ◽

Bingbing Wu ◽

...

Keyword(s):

Male Infertility ◽

Male Fertility ◽

Essential Role ◽

Coiled Coil ◽

Male Mice ◽

Sperm Tail ◽

Mouse Sperm ◽

Sperm Flagellum ◽

Coiled Coil Domain

Sperm flagellum is essential for male fertility, defects in flagellum biogenesis are associated with male infertility. Deficiency of CCDC42 is associated with malformation of the mouse sperm flagella. Here, we find that the testis-specific expressed protein CCDC38 (coiled coil domain containing 38) interacts with CCDC42 and localizes on manchette and sperm tail during spermiogenesis. Inactivation of CCDC38 in male mice results in distorted manchette, multiple morphological abnormalities of the flagella (MMAF) of spermatozoa, and eventually male sterility. Furthermore, we find that CCDC38 interacts with intra-flagellar transport protein 88 (IFT88) as well as the outer dense fibrous 2 (ODF2), and its depletion reduces the transportation of ODF2 to flagellum. Altogether, our results uncover the essential role of CCDC38 during sperm flagellum biogenesis, and suggesting the defects of these genes might be associated with male infertility in human being.

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Essential Role of the p110β Subunit of Phosphoinositide 3-OH Kinase in Male Fertility

Molecular Biology of the Cell ◽

10.1091/mbc.e09-08-0744 ◽

2010 ◽

Vol 21 (5) ◽

pp. 704-711 ◽

Cited By ~ 41

Author(s):

Elisa Ciraolo ◽

Fulvio Morello ◽

Robin M. Hobbs ◽

Frieder Wolf ◽

Romina Marone ◽

...

Keyword(s):

Male Fertility ◽

Essential Role ◽

Spermatogenic Cells ◽

Male Mice ◽

Catalytic Subunits ◽

Adult Testis ◽

New Treatments ◽

The Way

Phosphoinositide 3-kinases (PI3K) are key molecular players in male fertility. However, the specific roles of different p110 PI3K catalytic subunits within the spermatogenic lineage have not been characterized so far. Herein, we report that male mice expressing a catalytically inactive p110β develop testicular hypotrophy and impaired spermatogenesis, leading to a phenotype of oligo-azoospermia and defective fertility. The examination of testes from p110β-defective tubules demonstrates a widespread loss in spermatogenic cells, due to defective proliferation and survival of pre- and postmeiotic cells. In particular, p110β is crucially needed in c-Kit–mediated spermatogonial expansion, as c-Kit–positive cells are lost in the adult testis and activation of Akt by SCF is blocked by a p110β inhibitor. These data establish that activation of the p110β PI3K isoform by c-Kit is required during spermatogenesis, thus opening the way to new treatments for c-Kit positive testicular cancers.

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Essential role of CFAP53 in sperm flagellum biogenesis

10.1101/2021.02.04.429673 ◽

2021 ◽

Author(s):

Bingbing Wu ◽

Xiaochen Yu ◽

Chao Liu ◽

Lina Wang ◽

Tao Huang ◽

...

Keyword(s):

Male Fertility ◽

Essential Role ◽

Expression Level ◽

Research Progress ◽

Male Mice ◽

Sperm Tail ◽

Sperm Flagellum ◽

Associated Proteins ◽

Cilia And Flagella

AbstractThe sperm flagellum is essential for male fertility. Despite vigorous research progress towards understanding the pathogenesis of flagellum-related diseases, much remains unknown about the mechanisms underlying the flagellum biogenesis itself. Here, we show that the cilia and flagella associated protein 53 (Cfap53) gene is predominantly expressed in testes, and it is essential for sperm flagellum biogenesis. The knockout of this gene resulted in complete infertility in male mice but not in the females. CFAP53 localized to the manchette and sperm tail during spermiogenesis, the knockout of this gene impaired flagellum biogenesis. Furthermore, we identified two manchette and sperm tail-associated proteins that interacted with CFAP53 during spermiogenesis. The disruption of Cfap53 decreased the expression level of these two proteins and disrupted their localization in spermatids. Together, our results suggest that CFAP53 is an essential protein for sperm flagellum biogenesis, and its mutations might be associated with MMAF.

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SUN5 Interacting With Nesprin3 Plays an Essential Role in Sperm Head-to-Tail Linkage: Research on Sun5 Gene Knockout Mice

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.684826 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yunfei Zhang ◽

Linfei Yang ◽

Lihua Huang ◽

Gang Liu ◽

Xinmin Nie ◽

...

Keyword(s):

Molecular Mechanism ◽

Nuclear Membrane ◽

Knockout Mice ◽

Essential Role ◽

Gene Knockout ◽

Bioinformatic Analysis ◽

Sperm Head ◽

Linc Complex ◽

Absolute Quantitation ◽

Gene Knockout Mice

Acephalic spermatozoa syndrome is a rare genetic and reproductive disease. Recent studies have shown that approximately 33–47% of patients with acephalic spermatozoa syndrome have SUN5 mutations, but the molecular mechanism underlying this phenomenon has not been elucidated. In this study, we generated Sun5 knockout mice and found that the head-to-tail linkage was broken in Sun5–/– mice, which was similar to human acephalic spermatozoa syndrome. Furthermore, ultrastructural imaging revealed that the head-tail coupling apparatus (HTCA) and the centrosome were distant from the nucleus at steps 9–10 during spermatid elongation. With the manchette disappearing at steps 13–14, the head and the tail segregated. To explore the molecular mechanism underlying this process, bioinformatic analysis was performed and showed that Sun5 may interact with Nesprin3. Further coimmunoprecipitation (Co-IP) and immunofluorescence assays confirmed that Sun5 and Nesprin3 were indeed bona fide interaction partners that formed the linker of the nucleoskeleton and cytoskeleton (LINC) complex participating in the connection of the head and tail of spermatozoa. Nesprin3 was located posterior and anterior to the nucleus during spermiogenesis in wild-type mice, whereas it lost its localization at the implantation fossa of the posterior region in Sun5–/– mice. Without correct localization of Nesprin3 at the nuclear membrane, the centrosome, which is the originator of the flagellum, was distant from the nucleus, which led to the separation of the head and tail. In addition, isobaric tag for relative and absolute quantitation results showed that 47 proteins were upregulated, and 56 proteins were downregulated, in the testis in Sun5–/– mice, and the downregulation of spermatogenesis-related proteins (Odf1 and Odf2) may also contribute to the damage to the spermatozoa head-to-tail linkage. Our findings suggested that Sun5 is essential for the localization of Nesprin3 at the posterior nuclear membrane, which plays an essential role in the sperm head-tail connection.

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Essential Role of CFAP53 in Sperm Flagellum Biogenesis

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.676910 ◽

2021 ◽

Vol 9 ◽

Author(s):

Bingbing Wu ◽

Xiaochen Yu ◽

Chao Liu ◽

Lina Wang ◽

Tao Huang ◽

...

Keyword(s):

Male Fertility ◽

Essential Role ◽

Research Progress ◽

Male Mice ◽

Sperm Tail ◽

Morphological Abnormalities ◽

Sperm Flagellum ◽

Associated Proteins ◽

Cilia And Flagella

The sperm flagellum is essential for male fertility. Despite vigorous research progress toward understanding the pathogenesis of flagellum-related diseases, much remains unknown about the mechanisms underlying the flagellum biogenesis itself. Here, we show that the cilia and flagella associated protein 53 (Cfap53) gene is predominantly expressed in testes, and it is essential for sperm flagellum biogenesis. The knockout of this gene resulted in complete infertility in male mice but not in the females. CFAP53 localized to the manchette and sperm tail during spermiogenesis, the knockout of this gene impaired flagellum biogenesis. Furthermore, we identified two manchette and sperm tail-associated proteins that interacted with CFAP53 during spermiogenesis. Together, our results suggest that CFAP53 is an essential protein for sperm flagellum biogenesis, and its mutations might be associated with multiple morphological abnormalities of the flagella (MMAF).

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Technological Advancements in Male Infertility Microsurgery

Journal of Clinical Medicine ◽

10.3390/jcm10184259 ◽

2021 ◽

Vol 10 (18) ◽

pp. 4259

Author(s):

Nahid Punjani ◽

Caroline Kang ◽

Richard K. Lee ◽

Marc Goldstein ◽

Philip S. Li

Keyword(s):

Artificial Intelligence ◽

Male Infertility ◽

Essential Role ◽

New Technologies ◽

Education And Training ◽

History Of ◽

And Training ◽

Over Time

There have been significant advancements in male infertility microsurgery over time, and there continues to be significant promise for new and emerging techniques, technologies, and methodologies. In this review, we discuss the history of male infertility and the evolution of microsurgery, the essential role of education and training in male infertility microsurgery, and new technologies in this space. We also review the potentially important role of artificial intelligence (AI) in male infertility and microsurgery.

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Multiple mechanisms actively target the SUN protein UNC-84 to the inner nuclear membrane

Molecular Biology of the Cell ◽

10.1091/mbc.e10-08-0733 ◽

2011 ◽

Vol 22 (10) ◽

pp. 1739-1752 ◽

Cited By ~ 37

Author(s):

Erin C. Tapley ◽

Nina Ly ◽

Daniel A. Starr

Keyword(s):

Nuclear Envelope ◽

Nuclear Localization ◽

Nuclear Membrane ◽

Initial Step ◽

The Sun ◽

Nuclear Dynamics ◽

Nuclear Localization Signals ◽

Inner Nuclear Membrane ◽

Localization Signal ◽

Sorting Motif

Approximately 100 proteins are targeted to the inner nuclear membrane (INM), where they regulate chromatin and nuclear dynamics. The mechanisms underlying trafficking to the INM are poorly understood. The Caenorhabditis elegans SUN protein UNC-84 is an excellent model to investigate such mechanisms. UNC-84 recruits KASH proteins to the outer nuclear membrane to bridge the nuclear envelope (NE), mediating nuclear positioning. UNC-84 has four targeting sequences: two classical nuclear localization signals, an INM sorting motif, and a signal conserved in mammalian Sun1, the SUN—nuclear envelope localization signal. Mutations in some signals disrupt the timing of UNC-84 nuclear envelope localization, showing that diffusion is not sufficient to move all UNC-84 to the NE. Thus targeting UNC-84 requires an initial step that actively transports UNC-84 from the peripheral endoplasmic reticulum to the NE. Only when all four signals are simultaneously disrupted does UNC-84 completely fail to localize and to function in nuclear migration, meaning that at least three signals function, in part, redundantly to ensure proper targeting of UNC-84. Multiple mechanisms might also be used to target other proteins to the INM, thereby ensuring their proper and timely localization for essential cellular and developmental functions.

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NCOA5 Haplo-insufficiency Results in Male Mouse Infertility through Increased IL-6 Expression in the Epididymis

Scientific Reports ◽

10.1038/s41598-019-52105-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Shenglan Gao ◽

Yueqi Zhang ◽

Chengfeng Yang ◽

Gloria I. Perez ◽

Hua Xiao

Keyword(s):

Male Infertility ◽

Physiological Role ◽

Sperm Maturation ◽

Male Mice ◽

Heterozygous Deletion ◽

Epididymal Sperm ◽

Nuclear Receptor Coactivator ◽

Spermatozoa Motility ◽

Morphological Defects

Abstract Male infertility might be caused by genetic and/or environmental factors that impair spermatogenesis and epididymal sperm maturation. Here we report that heterozygous deletion of the nuclear receptor coactivator-5 (Ncoa5) gene resulted in decreased motility and progression of spermatozoa in the cauda epididymis, leading to infertility in male mice. Light microscopic and ultrastructural analysis revealed morphological defects in the spermatozoa collected from the cauda epididymis of Ncoa5+/− mice. Immunohistochemistry showed that interleukin-6 (IL-6) expression in epithelial cells of Ncoa5+/− epididymis was higher than wild type counterparts. Furthermore, heterozygous deletion of Il-6 gene in Ncoa5+/− male mice partially improved spermatozoa motility and moderately rescued infertility phenotype. Our results uncover a previously unknown physiological role of NCOA5 in the regulation of epididymal sperm maturation and suggest that NCOA5 deficiency could cause male infertility through increased IL-6 expression in epididymis.

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