Autophagy core protein ATG5 is required for elongating spermatid development, sperm individualization and normal fertility in male mice

Huang, Qian; Liu, Yunhao; Zhang, Shiyang; Yap, Yi Tian; Li, Wei; Zhang, David; Gardner, Ahmad; Zhang, Ling; Song, Shizheng; Hess, Rex A.; Zhang, Zhibing

doi:10.1080/15548627.2020.1783822

Cited by 76 publications

(44 citation statements)

References 66 publications

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“…These results indicated that autophagy activity was attenuated in MLE‐12 cells with the treatment of LPS. In addition, we measured the mRNA levels of Atg5 and Atg7, which were tightly associated with autophagosome formation (Huang et al, 2020). The results showed that Atg5 was significantly decreased both in vivo and in vitro (Figure 2c,d), suggesting that decreased expression of Atg5 might be responsible for the impairment of autophagy activity.…”

Section: Resultsmentioning

confidence: 99%

Metformin attenuates lipopolysaccharide‐induced epithelial cell senescence by activating autophagy

Wang

Chen

Sun

et al. 2021

Cell Biology International

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Acute lung injury (ALI) is a life‐threatening medical condition with higher mortality and morbidity in elderly patients. Recently, metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, has been shown to be an effective anti‐inflammatory agent in ALI. However, the mechanism of this regulation still remains poorly understood. In our study, we found that epithelial cell senescence was elevated after lipopolysaccharide (LPS) exposure in vivo and in vitro, accompanied by decreased expression of ATG5 and impaired autophagy activity. To further discover the molecular regulation mechanism between cellular senescence and autophagy in LPS‐treated MLE‐12 cells, we demonstrated that inhibition of ATG5 could decrease autophagy levels and promote the senescence of MLE‐12 cells. On the contrary, elevating the expression of ATG5 could effectively suppress LPS‐induced cellular senescence via enhancing autophagy activity. In addition, we demonstrated that metformin could protect MLE‐12 cells from LPS‐induced senescence via increasing the expression of ATG5 and augmenting autophagy activity. Our data implicate that activation of autophagy by metformin may provide a preventive and therapeutic strategy for ALI.

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Section: Resultsmentioning

confidence: 99%

Metformin attenuates lipopolysaccharide‐induced epithelial cell senescence by activating autophagy

Wang

Chen

Sun

et al. 2021

Cell Biology International

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“…Atg7 is homologous to the ubiquitin-activating enzyme E1 essential for the conjugation structures 112 , 113 . Atg7 mutant mice have aberrant round-headed spermatozoa with abnormal acrosome formation, which results from the failure of proacrosomal vesicle fusion and membrane trafficking 113 , 114 . In round spermatids, Gopc partially colocalized with sp56 on the acrosome but failed to localize to the acrosome in spermatids deficient in Atg7 115 , 116 .…”

Section: Spermiogenic Defects: Insight View From Mouse Modelsmentioning

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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“…Autophagy, a resource allocation process regulated by a series of factors, plays important roles in spermatogenesis. For instance, Atg7 is associated with acrosome formation, flagella biogenesis and cytoplasm removal 16 , 39 , and Atg5 plays roles in head and tail construction 40 ; Atg7 and Atg5 are also involved in testosterone synthesis 14 . However, the transcriptional signature of other autophagic genes and its significance in each cell type during human and mouse spermatogenesis remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…The current study revealed conserved and stage-specific patterns of autophagy-related genes during mouse and human spermatogenesis via single-cell transcriptome analysis. Besides, we provided an overview of classical autophagic gene transcription in spermatogenesis at single-cell resolution, mutations of these genes were reported to cause germ cell loss ( MTOR ) 43 or infertility ( LAMP2 ) 44 , suggesting the potential roles of other classical autophagic genes that were actively expressed in human spermatogonia ( AKT1 45 , ATG5 40 , EPG5 46 , TBC1D20 18 ), spermatocytes ( PRKACA 47 , ATG7 16 , SIRT1 17 , RARA 48 ) and spermatids ( TSC1 ) 49 . Moreover, comparison analysis of the stage-specific autophagic profiles between the testicular cells of fertile and infertile donors defined the pathologic factors contributing to dysregulated autophagy, providing potential targets for the development of new diagnostic and therapeutic approaches for male infertility 50 .…”

Section: Discussionmentioning

confidence: 99%

Deciphering the autophagy regulatory network via single-cell transcriptome analysis reveals a requirement for autophagy homeostasis in spermatogenesis

Wang¹,

Xu²,

Zhang³

et al. 2021

Theranostics

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Background: Autophagy has been implicated as a crucial component in spermatogenesis, and autophagy dysfunction can lead to reproductive disorders in animal models, including yeast, C. elegans and mice. However, the sophisticated transcriptional networks of autophagic genes throughout human spermatogenesis and their biological significance remain largely uncharacterized. Methods: We profiled the transcriptional signatures of autophagy-related genes during human spermatogenesis by assessing specimens from nine fertile controls (including two normal persons and seven obstructive azoospermia (OA) patients) and one nonobstructive azoospermia (NOA) patient using single-cell RNA sequencing (scRNA-seq) analysis. Dysregulation of autophagy was confirmed in two additional NOA patients by immunofluorescence staining. Gene knockdown was used to identify the role of Cst3 in autophagy during spermatogenesis. Results: Our data uncovered a unique, global stage-specific enrichment of autophagy-related genes. Human-mouse comparison analysis revealed that the stage-specific expression pattern of autophagy-related genes was highly conserved in mammals. More importantly, dysregulation of some clusters of autophagy-related genes was observed in NOA patients, suggesting the association of autophagy with male infertility. Cst3, a human-mouse conserved and autophagy-related gene that is actively expressed in spermatogonia and early spermatocytes, was found to regulate spermatogonial stem cell (SSC) maintenance and subsequent male germ cell development. Knockdown of Cst3 increased autophagic activity in mouse SSCs and subsequently suppressed the transcription of SSC core factors such as Oct4, Id1, and Nanos3, which could be efficiently rescued by manipulating autophagic activity. Conclusions: Our study provides comprehensive insights into the global transcriptional signatures of autophagy-related genes and confirms the importance of autophagy homeostasis in SSC maintenance and normal spermatogenesis, opening new avenues for further dissecting the significance of the autophagy regulatory network in spermatogenesis as well as male infertility.

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Autophagy core protein ATG5 is required for elongating spermatid development, sperm individualization and normal fertility in male mice

Cited by 76 publications

References 66 publications

Metformin attenuates lipopolysaccharide‐induced epithelial cell senescence by activating autophagy

Metformin attenuates lipopolysaccharide‐induced epithelial cell senescence by activating autophagy

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

Deciphering the autophagy regulatory network via single-cell transcriptome analysis reveals a requirement for autophagy homeostasis in spermatogenesis

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