Constitutive activation of NOTCH1 signaling in Sertoli cells causes gonocyte exit from quiescence.
Constitutive activation of NOTCH1 signaling in Sertoli cells causes gonocyte exit from quiescence.
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DOI：
10.1016/j.ydbio.2013.01.031
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发表时间：
2013-05-01
影响因子：
2.7
通讯作者：
Hofmann, Marie-Claude
中科院分区：
文献类型：
--
作者：
Garcia, Thomas Xavier;DeFalco, Tony;Capel, Blanche;Hofmann, Marie-Claude
Notch信号成分在发育和成熟睾丸的支持细胞和生殖细胞中早已被检测到。然而，这一途径在睾丸发育和精子发生中的作用仍不清楚。使用Notch受体激活后表达绿色荧光蛋白的报告小鼠，我们发现Notch信号在胎儿、新生儿和成人的各个阶段的支持细胞中是活跃的。由于Notch信号在许多发育和成熟的器官系统中指定干细胞的命运，我们假设生殖细胞和/或精原干细胞的维持和分化将通过支持细胞中的这一途径进行调节。为此，我们产生了突变小鼠组成型表达的活性，细胞内结构域的NOTCH 1（NICD 1）在支持细胞。我们发现突变的支持细胞在出生前后形态正常，但出现了一些功能变化，严重影响了生殖细胞的数量和生理。我们观察到生殖细胞从有丝分裂停滞中异常退出，向脐带外周迁移，以及出生前的过早分化。这些事件，大概不支持的细胞微环境，其次是生殖细胞凋亡和生殖细胞出生后第2天几乎完全消失。分子分析表明，这些影响与支持细胞表达的生殖细胞维持所需的基因（如Cyp 26 b1和GDNF）失调相关。两者合计，我们的研究结果表明，Notch信号是活跃的支持细胞在整个发展和适当的调节Notch信号在支持细胞是需要在胎儿发育过程中的未分化状态的生殖细胞的维护。
Notch signaling components have long been detected in Sertoli and germ cells in the developing and mature testis. However, the role of this pathway in testis development and spermatogenesis remains unknown. Using reporter mice expressing green fluorescent protein following Notch receptor activation, we found that Notch signaling was active in Sertoli cells at various fetal, neonatal, and adult stages. Since Notch signaling specifies stem cell fate in many developing and mature organ systems, we hypothesized that maintenance and differentiation of gonocytes and/or spermatogonial stem cells would be modulated through this pathway in Sertoli cells. To this end, we generated mutant mice constitutively expressing the active, intracellular domain of NOTCH1 (NICD1) in Sertoli cells. We found that mutant Sertoli cells were morphologically normal before and after birth, but presented a number of functional changes that drastically affected gonocyte numbers and physiology. We observed aberrant exit of gonocytes from mitotic arrest, migration toward cord periphery, and premature differentiation before birth. These events, presumably unsupported by the cellular microenvironment, were followed by gonocyte apoptosis and near complete disappearance of the gonocytes by day 2 after birth. Molecular analysis demonstrated that these effects are correlated with a dysregulation of Sertoli-expressed genes that are required for germ cell maintenance, such as Cyp26b1 and Gdnf. Taken together, our results demonstrate that Notch signaling is active in Sertoli cells throughout development and that proper regulation of Notch signaling in Sertoli cells is required for the maintenance of gonocytes in an undifferentiated state during fetal development.
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影响因子：
3.7
作者：
de Jonge HJ;Fehrmann RS;de Bont ES;Hofstra RM;Gerbens F;Kamps WA;de Vries EG;van der Zee AG;te Meerman GJ;ter Elst A
通讯作者：
ter Elst A
影响因子：
56.9
作者：
Bowles, J;Knight, D;Koopman, P
通讯作者：
Koopman, P
影响因子：
9.2
作者：
Bitgood, MJ;Shen, LY;McMahon, AP
通讯作者：
McMahon, AP
DOI：
10.1073/pnas.0308114100
发表时间：
2004-02-03
影响因子：
11.1
作者：
De Gendt, K;Swinnen, JV;Verhoeven, G
通讯作者：
Verhoeven, G
影响因子：
64.5
作者：
COFFMAN, CR;SKOGLUND, P;KINTNER, CR
通讯作者：
KINTNER, CR