The testis-specific LINC component SUN3 is essential for sperm head shaping during mouse spermiogenesis

Gao, Qian; Khan, Ranjha; Yu, Chang-Ping; Alsheimer, Manfred; Jiang, Xiaohua; Ma, Hui; Shi, Qinghua

doi:10.1074/jbc.ra119.012375

Cited by 49 publications

(58 citation statements)

References 42 publications

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“…Low sperm count with missing/mislocalized/fragmented acrosome, absence of manchette microtubules Mouse Globozoospermia-like [197] Sad1 and UNC84 domain containing 4 (SUN4)…”

Section: Human Mousementioning

confidence: 99%

Towards Post-Meiotic Sperm Production: Genetic Insight into Human Infertility from Mouse Models

Azhar¹,

Altaf²,

Uddin³

et al. 2021

Int. J. Biol. Sci.

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Declined quality and quantity of sperm is currently the major cause of patients suffering from infertility. Male germ cell development is spatiotemporally regulated throughout the whole developmental process. While it has been known that exogenous factors, such as environmental exposure, diet and lifestyle, et al, play causative roles in male infertility, recent progress has revealed abundant genetic mutations tightly associated with defective male germline development. In mammals, male germ cells undergo dramatic morphological change (i.e., nuclear condensation) and chromatin remodeling during post-meiotic haploid germline development, a process termed spermiogenesis; However, the molecular machinery players and functional mechanisms have yet to be identified. To date, accumulated evidence suggests that disruption in any step of haploid germline development is likely manifested as fertility issues with low sperm count, poor sperm motility, aberrant sperm morphology or combined. With the continually declined cost of next-generation sequencing and recent progress of CRISPR/Cas9 technology, growing studies have revealed a vast number of disease-causing genetic variants associated with spermiogenic defects in both mice and humans, along with mechanistic insights partially attained and validated through genetically engineered mouse models (GEMMs). In this review, we mainly summarize genes that are functional at post-meiotic stage. Identification and characterization of deleterious genetic variants should aid in our understanding of germline development, and thereby further improve the diagnosis and treatment of male infertility.

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“…Low sperm count with missing/mislocalized/fragmented acrosome, absence of manchette microtubules Mouse Globozoospermia-like [197] Sad1 and UNC84 domain containing 4 (SUN4)…”

Section: Human Mousementioning

confidence: 99%

Towards Post-Meiotic Sperm Production: Genetic Insight into Human Infertility from Mouse Models

Azhar¹,

Altaf²,

Uddin³

et al. 2021

Int. J. Biol. Sci.

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“…Sperm number, motility, and morphology were analyzed as previously described. 13,27,28 Hematoxylin and eosin (H&E) staining and periodic acid-Schiff (PAS)-hematoxylin staining were performed as we reported. 13 TUNEL assay was performed on testicular sections according to the manufacturer's instructions provided with in situ Cell Death Detection Kit (Roche).…”

Section: Phenotypic Analyses Of the Mouse Mutantsmentioning

confidence: 99%

Novel loss‐of‐function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice

et al. 2020

Self Cite

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Multiple morphological abnormalities of the flagella (MMAF) is a genetically heterogeneous disorder leading to male infertility. Recent studies have revealed that DNAH17 variants are associated with MMAF, yet there is no functional evidence in support of their pathnogenicity. Here, we recruited two consanguineous families of Pakistani and Chinese origins, respectively, diagnosed with MMAF. Whole-exome sequencing identified novel homozygous DNAH17 variants, which led to loss of DNAH17 proteins, in the patients. Transmission electron microscope analyses revealed completely disorganized axonemal structure as the predominant anomaly and increased frequencies of missings of microtubule doublet(s) 4-7 in sperm flagella of patients. Similar to those found in patients, Dnah17 −/− mice also displayed MMAF phenotype along with completely disorganized axonemal structures. Clusters of disorganized microtubules and outer dense fibers were observed in developing spermatids, indicating impaired sperm flagellar assembly. Besides, we also noticed many elongating spermatids with a deformed nuclear shape and abnormal step 16 spermatids that failed to spermiate, which subsequently underwent apoptosis in Dnah17-null mice. These findings present direct evidence establishing that DNAH17 is a MMAF-related gene in humans Beibei Zhang, Ihsan Khan, and Chunyu Liu contributed equally to this work.

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“…Regarding SUN3, it has been shown that Sun3 knockout male mice are infertile with a damaged sperm head and tail. In detail, the major abnormalities happen during spermiogenesis, where SPT nuclei fail to elongate due to the absence of cytoskeletal force transduction to NE, fundamental for head elongation [ 142 ]. As a consequence, the animals produce a low concentration of SPZ characterized by abnormal acrosome, low motility, and globozoospermia phenotype.…”

Section: Linc Complex and Male Infertilitymentioning

confidence: 99%

“…Pasch and coauthors demonstrate that SUN3 also participates in the connection of the manchette to NE by the heterotrimeric LINC complex SUN3/SUN4/KASH1 [ 45 ]. Accordingly, Sun3 knockout mice show a reduction of SUN4 levels in association to abnormal manchette formation [ 142 ]. Spermatogenesis of Sun4 knockout male mice normally progresses up to meiosis, but in the spermiogenesis phase, several post-meiotic aspects are compromised, leading to infertility.…”

Section: Linc Complex and Male Infertilitymentioning

confidence: 99%

LINCking the Nuclear Envelope to Sperm Architecture

Manfrevola

Guillou

Fasano

et al. 2021

Genes

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Nuclear architecture undergoes an extensive remodeling during spermatogenesis, especially at levels of spermatocytes (SPC) and spermatids (SPT). Interestingly, typical events of spermiogenesis, such as nuclear elongation, acrosome biogenesis, and flagellum formation, need a functional cooperation between proteins of the nuclear envelope and acroplaxome/manchette structures. In addition, nuclear envelope plays a key role in chromosome distribution. In this scenario, special attention has been focused on the LINC (linker of nucleoskeleton and cytoskeleton) complex, a nuclear envelope-bridge structure involved in the connection of the nucleoskeleton to the cytoskeleton, governing mechanotransduction. It includes two integral proteins: KASH- and SUN-domain proteins, on the outer (ONM) and inner (INM) nuclear membrane, respectively. The LINC complex is involved in several functions fundamental to the correct development of sperm cells such as head formation and head to tail connection, and, therefore, it seems to be important in determining male fertility. This review provides a global overview of the main LINC complex components, with a special attention to their subcellular localization in sperm cells, their roles in the regulation of sperm morphological maturation, and, lastly, LINC complex alterations associated to male infertility.

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The testis-specific LINC component SUN3 is essential for sperm head shaping during mouse spermiogenesis

Cited by 49 publications

References 42 publications

Towards Post-Meiotic Sperm Production: Genetic Insight into Human Infertility from Mouse Models

Towards Post-Meiotic Sperm Production: Genetic Insight into Human Infertility from Mouse Models

Novel loss‐of‐function variants in DNAH17 cause multiple morphological abnormalities of the sperm flagella in humans and mice

LINCking the Nuclear Envelope to Sperm Architecture

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