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PTEN signaling through RAF1 proto-oncogene serine/threonine kinase (RAF1)/ERK in the epididymis is essential for male fertility.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2014 Dec 30; Vol. 111 (52), pp. 18643-8. Date of Electronic Publication: 2014 Dec 15. - Publication Year :
- 2014
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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.
- Subjects :
- Animals
Cell Proliferation genetics
Cell Shape genetics
Extracellular Signal-Regulated MAP Kinases genetics
Gene Deletion
Hypertrophy enzymology
Hypertrophy genetics
Hypertrophy pathology
Male
Mice
Mice, Knockout
PTEN Phosphohydrolase genetics
Proto-Oncogene Proteins c-akt genetics
Proto-Oncogene Proteins c-akt metabolism
raf Kinases genetics
Epididymis enzymology
Extracellular Signal-Regulated MAP Kinases metabolism
Fertility physiology
MAP Kinase Signaling System physiology
PTEN Phosphohydrolase metabolism
raf Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 111
- Issue :
- 52
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 25512490
- Full Text :
- https://doi.org/10.1073/pnas.1413186112