p-MAPK1/3 and DUSP6 Regulate Epididymal Cell Proliferation and Survival in a Region-Specific Manner in Mice
p-MAPK1/3 and DUSP6 Regulate Epididymal Cell Proliferation and Survival in a Region-Specific Manner in Mice
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DOI：
10.1095/biolreprod.110.085613
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发表时间：
2010-11-01
影响因子：
3.6
通讯作者：
Hinton, Barry T.
中科院分区：
文献类型：
--
作者：
Xu, Bingfang;Yang, Ling;Hinton, Barry T.
一个完全发育的、有功能的附睾体对男性生育能力很重要。特别是，很明显，如果没有最近端的区域，即初始段(IS)，就会导致不孕。因此，了解这一重要附睾区的发育和调控是很重要的。我们以前已经证明IS的许多功能是由来自睾丸的管腔液体因子/光分泌因子调节的。本研究提供的证据表明，光分泌因子仅在出生后14天至19天的IS的上皮细胞中激活ERK通路，并将这种激活维持到成年。在发育中的IS中，激活的ERK通路促进了细胞的增殖和分化，而在成年IS中，它的作用被转换为维持细胞的存活。为了进一步了解IS中细胞增殖的调节，我们研究了DUSP6的作用，DUSP6是一种MAPK1/3(ERK1/2)偏好的磷酸酶，也受IS中的鲁米克林因子调节。利用Dusp6(-/-)小鼠，我们的研究令人惊讶地发现，Dusp6是头和体区细胞增殖的主要调节因子，而ERK通路的组件以及PTEN和SRC是IS中细胞增殖的主要调节因子。我们假设，细胞增殖的区域特异性调节是由每个附睾区促增殖和抗增殖信号通路成分之间活性平衡的差异引起的。对细胞增殖机制的了解可能会为附睾癌的发生提供线索。
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.