A heterozygous hypomorphic mutation of Fanca causes impaired follicle development and subfertility in female mice

Pan, Yuncheng; Yang, Xi; Zhang, Feng; Chen, Siyuan; Zhou, Zixue; Yin, Hong; Ma, Hui; Shang, Lingyue; Yang, Jialin; Li, Guoqing; Wang, Yingchen; Jin, Li; Shi, Qinghua; Wu, Yanhua

doi:10.1007/s00438-020-01730-5

Cited by 12 publications

(6 citation statements)

References 32 publications

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“…Six females were used in each group, and only one ovary was collected from each mouse. One in every five sections was stained with hematoxylin and eosin (H&E) for histological morphology observation and quantification as previously described ( 54 ). Representative pictures are shown.…”

Section: Methodsmentioning

confidence: 99%

Temporal transcriptomic landscape of postnatal mouse ovaries reveals dynamic gene signatures associated with ovarian aging

Zhou

Yang

Pan

et al. 2021

Human Molecular Genetics

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The ovary is the most important organ for maintaining female reproductive health, but it fails before most other organs. Aging-associated alterations in gene expression patterns in mammalian ovaries remain largely unknown. In this study, the transcriptomic landscape of postnatal mouse ovaries over the reproductive lifespan was investigated using bulk RNA sequencing in C57BL/6 mice. Gene expression dynamics revealed that the lifespan of postnatal mouse ovaries comprised four sequential stages, during which 2517 genes were identified as differentially enriched. Notably, the DNA repair pathway was found to make a considerable and specific contribution to the process of ovarian aging. Temporal gene expression patterns were dissected to identify differences in gene expression trajectories over the lifespan. In addition to DNA repair, distinct biological functions (including hypoxia response, epigenetic modification, fertilization, mitochondrial function, etc.) were overrepresented in particular clusters. Association studies were further performed to explore the relationships between known genes responsible for ovarian function and differentially expressed genes identified in this work. We found that the causative genes of human premature ovarian insufficiency were specifically enriched in distinct gene clusters. Taken together, our findings reveal a comprehensive transcriptomic landscape of the mouse ovary over the lifespan, providing insights into the molecular mechanisms underlying mammalian ovarian aging and supporting future etiological studies of aging-associated ovarian disorders.

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Section: Methodsmentioning

confidence: 99%

Temporal transcriptomic landscape of postnatal mouse ovaries reveals dynamic gene signatures associated with ovarian aging

Zhou

Yang

Pan

et al. 2021

Human Molecular Genetics

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“…Fanca KO mice have been reported to display growth retardation, impaired follicle development, and immature hematopoietic stem cell development. 42 But the function and regulation of FANCA in VSMCs and vascular development is unknown. Our data showed that FANCA mediated VSMC proliferation through dictating cell cycle.…”

Section: Discussionmentioning

confidence: 99%

DDX24 Is Essential for Cell Cycle Regulation in Vascular Smooth Muscle Cells During Vascular Development via Binding to FANCA mRNA

Gong

Liang

Liu

et al. 2023

ATVB

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BACKGROUND: The DEAD-box family is essential for tumorigenesis and embryogenesis. Previously, we linked the malfunction of DDX (DEAD-box RNA helicase)-24 to a special type of vascular malformation. Here, we aim to investigate the function of DDX24 in vascular smooth muscle cells (VSMCs) and embryonic vascular development. METHODS: CMC/VSMC-specific Ddx24 knockout mice were generated by crossing Tagln -Cre mice with Ddx24 flox/flox transgenic mice. The development of blood vessels was explored by stereomicroscope photography and immunofluorescence staining. Flow cytometry and cell proliferation assays were used to verify the regulation of DDX24 on the function of VSMCs. RNA sequencing and RNA immunoprecipitation quantitative real-time polymerase chain reaction were combined to investigate DDX24 downstream regulatory molecules. RNA pull-down and RNA stability experiments were performed to explore the regulation mechanism of DDX24. RESULTS: CMC/VSMC-specific Ddx24 knockout mice died before embryonic day 13.5 with defects in vessel formation and abnormal vascular remodeling in extraembryonic tissues. Ddx24 knockdown suppressed VSMC proliferation via cell cycle arrest, likely due to increased DNA damage. DDX24 protein bound to and stabilized the mRNA of FANCA (FA complementation group A) that responded to DNA damage. Consistent with the function of DDX24, depletion of FANCA also impacted cell cycle and DNA repair of VSMCs. Overexpression of FANCA was able to rescue the alterations caused by DDX24 deficiency. CONCLUSIONS: Our study unveiled a critical role of DDX24 in VSMC-mediated vascular development, highlighting a potential therapeutic target for VSMC-related pathological conditions.

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“…Furthermore, the majority of the mice lost their fertility with age. The results of a series of experiments showed that FANCA -mutant mice demonstrated considerably reduced fertility due to insufficient or damaged ovarian follicular reserve [88]. Furthermore, in another experiment that established FANCA knockout mice using a gene-targeting method, the fertility of the experimental mice tended to decrease, and almost no follicles were observed in the ovaries of a small number of mice over time, thereby resulting in severe infertility [89].…”

Section: Role Of Fa Genes In Poi Occurrencementioning

confidence: 99%

Research progress of the Fanconi anemia pathway and premature ovarian insufficiency

Zhao,

Zhang,

et al. 2023

Biology of Reproduction

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The Fanconi anemia pathway is a key pathway involved in the repair of deoxyribonucleic acidinterstrand crosslinking damage, which chiefly includes the following four modules: lesion recognition, Fanconi anemia core complex recruitment, FANCD2–FANCI complex monoubiquitination, and downstream events (nucleolytic incision, translesion synthesis, and homologous recombination). Mutations or deletions of multiple Fanconi anemia genes in this pathway can damage the interstrand crosslinking repair pathway and disrupt primordial germ cell development and oocyte meiosis, thereby leading to abnormal follicular development. Premature ovarian insufficiency is a gynecological clinical syndrome characterized by amenorrhea and decreased fertility due to decreased oocyte pool, accelerated follicle atresia, and loss of ovarian function in women <40 years old. Furthermore, in recent years, several studies have detected mutations in the Fanconi anemia gene in patients with premature ovarian insufficiency. In addition, some patients with Fanconi anemia exhibit symptoms of premature ovarian insufficiency and infertility. The Fanconi anemia pathway and premature ovarian insufficiency are closely associated.

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A heterozygous hypomorphic mutation of Fanca causes impaired follicle development and subfertility in female mice

Cited by 12 publications

References 32 publications

Temporal transcriptomic landscape of postnatal mouse ovaries reveals dynamic gene signatures associated with ovarian aging

Temporal transcriptomic landscape of postnatal mouse ovaries reveals dynamic gene signatures associated with ovarian aging

DDX24 Is Essential for Cell Cycle Regulation in Vascular Smooth Muscle Cells During Vascular Development via Binding to FANCA mRNA

Research progress of the Fanconi anemia pathway and premature ovarian insufficiency

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