ACTN4 Mediates SEPT14 Mutation-Induced Sperm Head Defects

Lin, Yu-Hua; Huang, Chia-Yen; Ke, Chih-Chun; Wang, Yayun; Lai, Tsung‐Ching; Liu, Hsuan-Che; Ku, Wei-Chi; Chan, Chying-Chyuan; Lin, Ying-Hung

doi:10.3390/biomedicines8110518

Cited by 9 publications

(8 citation statements)

References 61 publications

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“…Interestingly, SEPT12 interacts with the SUNdomain-containing nuclear membrane protein SPAG4 and may Review therefore link the spermatid nucleus to microtubules 135 . SEPT14 also interacts with a-actinin-4 at the nuclear envelope and the manchette and might link both microtubules and actin to the nuclear membrane 136 . Septins have been similarly implicated in linking microtubules to the plasma membrane.…”

Section: Roles Of Microtubule-associated Septins In Cellular Morphogenesismentioning

confidence: 99%

Cellular functions of actin- and microtubule-associated septins

2021

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Section: Roles Of Microtubule-associated Septins In Cellular Morphogenesismentioning

confidence: 99%

Cellular functions of actin- and microtubule-associated septins

2021

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“…In our previous study, we discovered that the mutated SEPT14 resulted in teratozoospermia (n = 6), with >14% spermatozoa retaining their normal morphology [ 29 ]. We further identified SEPT14 interactors, a peptide of RAB3B/C [ 30 ]. In this study, Figure 1 and Supplementary Figure S2 suggest that RAB 3C is a major component of human sperm formation within the RAB3 family, and there is no RAB3B signal.…”

Section: Resultsmentioning

confidence: 99%

“…In our previous studies, we identified mutations in the SEPT12 and SEPT14 genes by sequencing their coding regions and showed that they caused severe sperm head deformation and DNA damage in male infertility cases [ 26 , 29 ]. We also found that SEPT12 and SEPT14 form filamentous structures and assist in sperm head shaping and tail elongation during human spermiogenesis [ 25 , 26 , 29 , 30 , 55 ]. SEPT12 or SEPT14 mutations disrupt filamentous structures, causing morphological defects in sperm and DNA damage [ 25 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…In our previous studies, we also observed that two SEPT14 mutations cause teratozoospermia, with defects mainly in the sperm head [ 29 ]. Furthermore, we identified SEPT14 interactors through co-immunoprecipitation and nano-liquid chromatography-mass spectrometry/mass spectrometry [ 30 ]. One such peptide belongs to RAB3B and RAB3C; the amino acid sequences of RAB3B and RAB3C are highly similar.…”

Section: Introductionmentioning

confidence: 99%

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Localization Patterns of RAB3C Are Associated with Murine and Human Sperm Formation

et al. 2022

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Background and Objectives: Septins (SEPTs) are highly conserved GTP-binding proteins and the fourth component of the cytoskeleton. Polymerization of SEPTs contributes to several critical cellular processes such as cytokinesis, cytoskeletal remodeling, and vesicle transportation. In our previous study, we found that SEPT14 mutations resulted in teratozoospermia with >87% sperm morphological defects. SEPT14 interactors were also identified through proteomic assays, and one of the peptides was mapped to RAB3B and RAB3C. Most studies on the RAB3 family have focused on RAB3A, which regulates the exocytosis of neurotransmitters and acrosome reactions. However, the general expression and patterns of the RAB3 family members during human spermatogenesis, and the association between RAB3 and teratozoospermia owing to a SEPT14 mutation, are largely unknown. Material and Methods: Human sperm and murine male germ cells were collected in this study and immunofluorescence analysis was applied on the collected sperm. Results: In this study, we observed that the RAB3C transcripts were more abundant than those of RAB3A, 3B, and 3D in human testicular tissues. During human spermatogenesis, the RAB3C protein is mainly enriched in elongated spermatids, and RAB3B is undetectable. In mature human spermatozoa, RAB3C is concentrated in the postacrosomal region, neck, and midpiece. The RAB3C signals were delocalized within human spermatozoa harboring the SEPT14 mutation, and the decreased signals were accompanied by a defective head and tail, compared with the healthy controls. To determine whether RAB3C is involved in the morphological formation of the head and tail of the sperm, we separated murine testicular tissue and isolated elongated spermatids for further study. We found that RAB3C is particularly expressed in the manchette structure, which assists sperm head shaping at the spermatid head, and is also localized at the sperm tail. Conclusion: Based on these results, we suggest that the localization of RAB3C proteins in murine and human sperm is associated with SEPT14 mutation-induced morphological defects in sperm.

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“…Correspondingly, SEPT12 mutations have been described in infertile men displaying abnormal sperm including defective annulus with a bent tail (Kuo et al 2012). Additionally, defective sperm head morphology and DNA integrity have recently been reported for two different SEPT14 missense mutations (Wang et al 2019, Lin et al 2020). Previous findings proposed a septin ring assembly as octameric filaments at the annulus, classically composed of septins 12-7-6-2-2-6-7-12 or 12-7-6-4-4-6-7-12, in which septins 12 and 7 and septins 6 and 2/4 are connected through their GTP-binding domain (G-interface), whereas septins 7 and 6 and the two central septins 2/4 interact via their NC-termini (NC-interface) (Sirajuddin et al 2007, Kuo et al 2015).…”

Section: Discussionmentioning

confidence: 99%

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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ACTN4 Mediates SEPT14 Mutation-Induced Sperm Head Defects

Cited by 9 publications

References 61 publications

Cellular functions of actin- and microtubule-associated septins

Cellular functions of actin- and microtubule-associated septins

Localization Patterns of RAB3C Are Associated with Murine and Human Sperm Formation

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

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