ArticleProceedings of the National Academy of Sciences of the United States of America2014
PTEN signaling through RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is essential for male fertility.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 40 citations in OpenAlex.
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- RUNX transcription factors are essential in maintaining epididymal epithelial differentiation.Cellular and molecular life sciences : CMLS · 2024Article
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- Epithelial and mesenchymal fate decisions in Wolffian duct development.Trends in endocrinology and metabolism: TEM · 2023Review
- Erianin suppresses constitutive activation of MAPK signaling pathway by inhibition of CRAF and MEK1/2.Signal transduction and targeted therapy · 2023Article
- Differential gene expression and hallmarks of stemness in epithelial cells of the developing rat epididymis.Cell and tissue research · 2022Article
- Ribosomal Protein S6: A Potential Therapeutic Target against Cancer?International journal of molecular sciences · 2021Review
- NCOA5 Haplo-insufficiency Results in Male Mouse Infertility through Increased IL-6 Expression in the Epididymis.Scientific reports · 2019Article
- Comparative Transcriptomic Analysis Reveals Molecular Profiles of Central Nervous System in Maternal Diapause Induction ofG3 (Bethesda, Md.) · 2019Article
- A tale of two tracts: history, current advances, and future directions of research on sexual differentiation of reproductive tracts†.Biology of reproduction · 2019Review
- Alteration of transporter activities in the epididymides of infertile initial segment-specific Pten knockout mice.Biology of reproduction · 2018Article
- Molecular changes and signaling events occurring in spermatozoa during epididymal maturation.Andrology · 2017Review
- Small RNA sequencing of cryopreserved semen from single bull revealed altered miRNAs and piRNAs expression between High- and Low-motile sperm populations.BMC genomics · 2017Article
- Functional Role and Mechanism of microRNA-28b in Atrial Myocyte in a Persistent Atrial Fibrillation Rat Model.Medical science monitor : international medical journal of experimental and clinical research · 2016Article
- Initial Segment Differentiation Begins During a Critical Window and Is Dependent upon Lumicrine Factors and SRC Proto-Oncogene (SRC) in the Mouse.Biology of reproduction · 2016Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Without a fully developed initial segment, the most proximal region of the epididymis, male infertility results. Therefore, it is important to understand the development and regulation of this crucial region. In addition to distinctively high activity levels of the components of the ERK pathway, which are essential for initial-segment differentiation, the initial segment exhibits high protein and activity levels of phosphatase and tensin homolog (PTEN). To understand the role of PTEN in the regulation of the initial segment, we generated a mouse model with a conditional deletion of Pten from the epithelial cells of the proximal epididymis from postnatal day 17 (P17) onward. Shortly after Pten deletion, hypertrophy of the proximal epididymis became evident. Loss of Pten resulted in activation of the AKT (protein kinase B) pathway components from P28 onward, which in turn gradually suppressed RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK signaling through the interaction between AKT and RAF1. Consistent with progressive changes in RAF1/ERK signaling, loss of Pten progressively altered cell shape, size, organization, proliferation, and survival in the initial-segment epithelium and resulted in dedifferentiation and extensive epithelial folding. Most importantly, knockout males progressively lost fertility and became infertile from 6 to 12 mo. Spermatozoa from older knockout mice showed a lower percentage of motility and a higher percentage of flagellar angulation compared with controls, suggesting compromised sperm maturation. Therefore, under normal physiological conditions, PTEN suppresses AKT activity to maintain activation of the RAF1/ERK signaling pathway, which in turn maintains normal function of the initial segment and therefore, normal sperm maturation.
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