IGF2BP1 stabilizes Akt2 mRNA to promote glucose metabolism and maintain spermatogonial proliferation.

IF 3.7 3区生物学 Q1 DEVELOPMENTAL BIOLOGY

Reproduction Pub Date : 2025-03-03 Print Date: 2025-04-01 DOI:10.1530/REP-24-0202

Yanan Liu, Yuanyuan Chen, Jiahui Fan, Ziqian Min, Xiaowen Liu, Zenghui Mao, Anji Chen, Min Liu, Rong Xia, Lifang Yang, Dan Li

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引用次数: 0

Abstract

In brief: The dysregulation of spermatogonial proliferation is one of the causes of male infertility. Using mice as an animal model, this study reveals the function and mechanism of m6A methylation reader insulin-like growth factor-2 mRNA-binding protein 1 (IGF2BP1) and its target Akt2 in spermatogonia.

Abstract: IGF2BP1, as a newly identified N6-methyladenosine (m6A) methylation reader, plays a key role in mRNA stability, alternative splicing and translation. However, the function of IGF2BP1 and its target genes in the development of male germ cells remains unclear. In the present study, Western blotting, immunofluorescence and other cellular methods were used to confirm that IGF2BP1 is expressed throughout the male germline with high abundance in spermatogonia of mice, and that its downregulation inhibits spermatogonia proliferation in vitro. Through RNA sequencing, dual luciferase reporter assays, RIP-qPCR and mRNA stability experiments, it was identified that Akt2 is one of the target genes of IGF2BP1. By stabilizing Akt2 mRNA in an m6A-dependent manner, IGF2BP1 maintains spermatogonial proliferation. Furthermore, co-immunoprecipitation and mass spectrometry analyses revealed that PABPC1, DDX5 and FXR1 interact with IGF2BP1, and that the interaction between IGF2BP1 and PABPC1 promotes AKT2 expression. Finally, following the knockdown of both IGF2BP1 and AKT2, glucose and ATP levels in C18-4 and GC-1 spermatogonia cells were found to be reduced, indicating that IGF2BP1 regulates glucose metabolism homeostasis by stabilizing Akt2 expression, thereby influencing spermatogonia proliferation. In addition, analysis of the cryptorchidism database from NCBI revealed that the expression of IGF2BP1 and AKT2 is significantly downregulated in cryptorchid patients with oligospermia or azoospermia. In conclusion, our study elucidates the role and underlying mechanism of IGF2BP1 in spermatogonia, providing a candidate target for male infertility.

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来源期刊

Reproduction 生物-发育生物学

CiteScore

7.40

自引率

2.60%

发文量

199

审稿时长

4-8 weeks

期刊介绍： Reproduction is the official journal of the Society of Reproduction and Fertility (SRF). It was formed in 2001 when the Society merged its two journals, the Journal of Reproduction and Fertility and Reviews of Reproduction. Reproduction publishes original research articles and topical reviews on the subject of reproductive and developmental biology, and reproductive medicine. The journal will consider publication of high-quality meta-analyses; these should be submitted to the research papers category. The journal considers studies in humans and all animal species, and will publish clinical studies if they advance our understanding of the underlying causes and/or mechanisms of disease. Scientific excellence and broad interest to our readership are the most important criteria during the peer review process. The journal publishes articles that make a clear advance in the field, whether of mechanistic, descriptive or technical focus. Articles that substantiate new or controversial reports are welcomed if they are noteworthy and advance the field. Topics include, but are not limited to, reproductive immunology, reproductive toxicology, stem cells, environmental effects on reproductive potential and health (eg obesity), extracellular vesicles, fertility preservation and epigenetic effects on reproductive and developmental processes.