p-MAPK1/3 and DUSP6 regulate epididymal cell proliferation and survival in a region-specific manner in mice.
A fully developed, functional epididymis is important for male fertility. In particular, it is apparent that without the most proximal region, the initial segment (IS), infertility results. Therefore, it is important to understand the development and regulation of this crucial epididymal region. We have previously shown that many functions of the IS are regulated by luminal fluid factors/lumicrine factors from the testis. This study provides evidence that lumicrine factors activated the ERK pathway only in epithelial cells of the IS from Postnatal Day (P) 14 to P19 and sustained this activation into adulthood. The activated ERK pathway promoted cell proliferation and differentiation in the developing IS, although in the adult, its role was switched to maintain cell survival. To understand further the regulation of cell proliferation in the IS, we examined the role of DUSP6, an MAPK1/3 (ERK1/2) preferred phosphatase that is also regulated by lumicrine factors in the IS. Utilizing Dusp6(-/-) mice, our studies, surprisingly, revealed that Dusp6 was a major regulator of cell proliferation in the caput and corpus regions, whereas components of the ERK pathway, together with PTEN and SRC, were the major regulators of cell proliferation in the IS. We hypothesize that region-specific regulation of cell proliferation is caused by differences in the balance of activities between pro- and antiproliferation signaling pathway components for each epididymal region. An understanding of the mechanisms of cell proliferation may provide clues as to why the epididymis rarely succumbs to cancer.
Xu
Bingfang
B
Department of Cell Biology, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Yang
Ling
L
Lye
R John
RJ
Hinton
Barry T
BT
D000375:Aging; D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000502:physiology*; D004822:Epididymis / Q000166:cytology / Q000254:growth & development / Q000502:physiology* / Q000601:surgery; D018507:Gene Expression Regulation, Developmental; D016391:Genes, src / Q000502:physiology; D008026:Ligation; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D009928:Organ Specificity; D051059:PTEN Phosphohydrolase / Q000502:physiology; D010766:Phosphorylation; D040081:Protein Array Analysis; D012333:RNA, Messenger / Q000378:metabolism; D013735:Testicular Hormones / Q000502:physiology
D012333:RNA, Messenger; D013735:Testicular Hormones; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse