The SEPT12 complex is required for the establishment of a functional sperm head–tail junction

Shen, Yi Ru; Wang, Han Yu; Tsai, Yung Chieh; Kuo, Yung Che; Wu, Shang; Wang, Chia‐Yih; Kuo, Pao Lin

doi:10.1093/molehr/gaaa031

Cited by 12 publications

(7 citation statements)

References 43 publications

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“…These data suggest that the upregulated expression and annular localization of sAC are important for sperm capacitation and male fertility. SEPT12 forms complexes in the sperm neck (Shen et al, 2020). In this study, we that SEPT4 was not located in the sperm neck, suggesting that SEPT12 orchestrated septin complexes in the sperm neck were independent of SEPT4.…”

Section: Discussionmentioning

confidence: 61%

Proper phosphorylation of septin 12 regulates septin 4 and soluble adenylyl cyclase expression to induce sperm capacitation

Wang

Shen

Tsai

et al. 2023

Journal Cellular Physiology

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Septin‐based ring complexes maintain the sperm annulus. Defective annular structures are observed in the sperm of Sept12‐ and Sept4‐null mice. In addition, sperm capacitation, a process required for proper fertilization, is inhibited in Sept4‐null mice, implying that the sperm annulus might play a role in controlling sperm capacitation. Hence, we analyzed sperm capacitation of sperm obtained from SEPT12 Ser196 phosphomimetic (S196E), phosphorylation‐deficient (S196A), and SEPT4‐depleted mutant mice. Capacitation was reduced in the sperm of both the Sept12 S196E‐ and Sept12 S196A‐knock‐in mice. The protein levels of septins, namely, SEPT4 and SEPT12, were upregulated, and these proteins were concentrated in the sperm annulus during capacitation. Importantly, the expression of soluble adenylyl cyclase (sAC), a key enzyme that initiates capacitation, was upregulated, and sAC was recruited to the sperm annulus following capacitation stimulation. We further found that SEPT12, SEPT4, and sAC formed a complex and colocalized to the sperm annulus. Additionally, sAC expression was reduced and disappeared in the annulus of the SEPT12 S196E‐ and S196A‐mutant mouse sperm. In the sperm of the SEPT4‐knockout mice, sAC did not localize to the annulus. Thus, our data demonstrate that SEPT12 phosphorylation status and SEPT4 activity jointly regulate sAC protein levels and annular localization to induce sperm capacitation.

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Section: Discussionmentioning

confidence: 61%

Proper phosphorylation of septin 12 regulates septin 4 and soluble adenylyl cyclase expression to induce sperm capacitation

Wang

Shen

Tsai

et al. 2023

Journal Cellular Physiology

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“…Two mutations of Sept12 identified in patients disrupted the complex, leading to unstable head-tail junctions and defective connecting piece formation. Strikingly, the mutation of Sept12 and the subsequent disruption of the complex led to loss of Sept10 signal in the annulus (Shen et al 2020) as also observed in Adgb-deficient mice. Accordingly, our data suggest an interdependence between Adgb and Sept10, which is required for the maintenance of the annulus, head shaping and proper mitochondrial localisation.…”

Section: Discussionmentioning

confidence: 65%

Androglobin, a chimeric mammalian globin, is required for male fertility

Keppner

Correia

Santambrogio

et al. 2021

Preprint

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Spermatogenesis is a highly specialised process, involving multiple dedicated pathways and regulatory check-points. Defects ultimately lead to male sub-fertility or sterility, and numerous aspects of mammalian sperm formation remain unknown. The predominant expression of the latest globin family member, androglobin (Adgb) in mammalian testis tissue prompted us to assess its physiological function in spermatogenesis. Adgb knockout mice display male infertility, reduced testis weight, impaired maturation of elongating spermatids, abnormal sperm shape and ultrastructural defects in microtubule and mitochondrial organisation. Epididymal sperm from Adgb knockout animals display multiple flagellar malformations including coiled, bifide or shortened flagella, and erratic acrosomal development. Following immunoprecipitation and mass spectrometry, we could identify septin 10 (Sept10) as interactor of Adgb. The Sept10-Adgb interaction was confirmed both in vivo using testis lysates, and in vitro by reciprocal co-immunoprecipitation experiments. Furthermore, absence of Adgb leads to mislocalisation of Sept10 in sperm, indicating defective manchette and sperm annulus formation. Finally, in vitro data suggest that Adgb contributes to Sept10 proteolysis in a calmodulin (CaM)-dependent manner. Collectively, our results provide evidence that Adgb is essential for murine spermatogenesis and further suggest that interdependence between Adgb and Sept10 is required for sperm head shaping via the manchette and proper flagellum formation.

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“…It is expressed specifically in testis, and located in the neck and annulus regions of mature sperm ( Shen et al, 2017 ). SEPTIN12 forms complexes with other SEPTINs , 1, 2, 10 and 11 at the sperm neck, and 1, 4, 6 and 7 at the annulus, and is essential for the assembly of the connecting pieces and the annulus ( Toure et al, 2011 ; Shen et al, 2017 ; Shen et al, 2020 ). It was first identified as a down-regulated gene in the testicular tissue of infertile men ( Lin et al, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

Homozygous Loss of Septin12, but not its Haploinsufficiency, Leads to Male Infertility and Fertilization Failure

Chen

Zhao

et al. 2022

Front. Cell Dev. Biol.

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The SEPTIN12 gene has been associated with male infertility. Male Septin12+/− chimera mice were infertile, supporting the prevailing view that SEPTIN12 haploinsufficiency causes male infertility. In this study, we identified a heterozygous mutation on SEPTIN12, c.72C>A (p.Cys24Ter) in the male partner of a patient couple, who had a previous fertilization failure (FF) after intracytoplasmic sperm injection (ICSI) and became pregnant after ICSI together with artificial oocyte activation (AOA). To investigate the role of SEPTIN12 in FF and oocyte activation, we constructed Septin12 knockout mice. Surprisingly, Septin12−/− male mice, but not Septin12+/− male mice, are infertile, and have reduced sperm counts and abnormal sperm morphology. Importantly, AOA treatment enhances the 2-cell embryo rate of ICSI embryos injected with Septin12−/− sperm, indicating that FF caused by male Septin12 deficiency is overcome by AOA. Mechanistically, loss of PLCζ around the acrosome might be the reason for FF of Septin12−/− sperm. Taken together, our data indicated that homozygous knockout of Septin12, but not Septin12 haploinsufficiency, leads to male infertility and FF.

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The SEPT12 complex is required for the establishment of a functional sperm head–tail junction

Cited by 12 publications

References 43 publications

Proper phosphorylation of septin 12 regulates septin 4 and soluble adenylyl cyclase expression to induce sperm capacitation

Proper phosphorylation of septin 12 regulates septin 4 and soluble adenylyl cyclase expression to induce sperm capacitation

Androglobin, a chimeric mammalian globin, is required for male fertility

Homozygous Loss of Septin12, but not its Haploinsufficiency, Leads to Male Infertility and Fertilization Failure

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