Estrogen-dependent proteolytic cleavage of semaphorin 4D and plexin-B1 enhances semaphorin 4D-induced apoptosis during postnatal vaginal remodeling in pubescent mice.
Estrogen-dependent proteolytic cleavage of semaphorin 4D and plexin-B1 enhances semaphorin 4D-induced apoptosis during postnatal vaginal remodeling in pubescent mice.
复制标题
DOI：
10.1371/journal.pone.0097909
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Yukawa K
中科院分区：
文献类型：
--
作者：
Ito T;Bai T;Tanaka T;Yoshida K;Ueyama T;Miyajima M;Negishi T;Kawasaki T;Takamatsu H;Kikutani H;Kumanogoh A;Yukawa K
在出生后的第五周左右，雌性小鼠幼崽的阴道腔向覆盖的皮肤打开。这种生殖道的出生后组织重塑发生在青春期，它在很大程度上取决于阴道诱导的细胞凋亡，主要发生在小鼠阴道腔下部的上皮细胞中。以前，我们发现，大多数BALB/c小鼠缺乏IV类Semaphorin（Sema 4D）发展imperial阴道和子宫阴道积水;因此，我们推断，在阴道上皮细胞中缺乏Sema 4D诱导的细胞凋亡可能导致imperial阴道。Sema 4D信号通过丛蛋白-B1受体;然而，详细的机制介导这种神经元引发的细胞凋亡没有完全记录。为了研究雌激素依赖性的控制Sema 4D信号在负责小鼠阴道开口的细胞凋亡过程中，我们通过分析野生型和Sema 4D −/−小鼠（有或没有卵巢切除术）来研究Sema 4D，丛蛋白B1和信号分子的结构和功能调节。可溶性Sema 4D的释放和阴道组织中通过蛋白水解加工的丛蛋白-B1的转化在野生型BALB/c小鼠出生后5周阴道开放时达到峰值。卵巢切除的野生型小鼠补充雌激素后发现，可溶性Sema 4D的释放和丛蛋白-B1转化为活性形式都是雌激素依赖性的，并且与细胞凋亡一致。雌激素补充卵巢切除Sema 4D −/−小鼠没有诱导大量的阴道细胞凋亡在5周龄的小鼠;因此，Sema 4D可能是一个重要的前列腺增生诱导配体，作用于雌激素作用的下游在阴道上皮细胞在这个产后组织重塑。卵巢切除小鼠的分析也表明，Sema 4D有助于雌激素依赖性的Akt和ERK的去磷酸化在阴道开口的时间。基于我们的研究结果，我们提出，在出生后阴道开口阴道上皮细胞凋亡诱导增强Sema 4D信号，这是由雌激素依赖性结构变化的Sema 4D和丛蛋白-B1。
Around the fifth week after birth, the vaginal cavity in female mouse pups opens to the overlaying skin. This postnatal tissue remodeling of the genital tract occurs during puberty, and it largely depends upon hormonally induced apoptosis that mainly occurs in the epithelium at the lower part of the mouse vaginal cavity. Previously, we showed that most BALB/c mice lacking the class IV Semaphorin (Sema4D) develop imperforate vagina and hydrometrocolpos; therefore, we reasoned that the absence of Sema4D-induced apoptosis in vaginal epithelial cells may cause the imperforate vagina. Sema4D signals via the Plexin-B1 receptor; nevertheless detailed mechanisms mediating this hormonally triggered apoptosis are not fully documented. To investigate the estrogen-dependent control of Sema4D signaling during the apoptosis responsible for mouse vaginal opening, we examined structural and functional modulation of Sema4D, Plexin-B1, and signaling molecules by analyzing both wild-type and Sema4D−/− mice with or without ovariectomy. Both the release of soluble Sema4D and the conversion of Plexin-B1 by proteolytic processing in vaginal tissue peaked 5 weeks after birth of wild-type BALB/c mice at the time of vaginal opening. Estrogen supplementation of ovariectomized wild-type mice revealed that both the release of soluble Sema4D and the conversion of Plexin-B1 into an active form were estrogen-dependent and concordant with apoptosis. Estrogen supplementation of ovariectomized Sema4D−/− mice did not induce massive vaginal apoptosis in 5-week-old mice; therefore, Sema4D may be an essential apoptosis-inducing ligand that acts downstream of estrogen action in vaginal epithelium during this postnatal tissue remodeling. Analysis of ovariectomized mice also indicated that Sema4D contributed to estrogen-dependent dephosphorylation of Akt and ERK at the time of vaginal opening. Based on our results, we propose that apoptosis in vaginal epithelium during postnatal vaginal opening is induced by enhanced Sema4D signaling that is caused by estrogen-dependent structural changes of Sema4D and Plexin-B1.
登录
查看更多内容
影响因子：
4.8
作者：
Basile, John R.;Gavard, Julie;Gutkind, J. Silvio
通讯作者：
Gutkind, J. Silvio
影响因子：
7.8
作者：
Giacobini, Paolo;Messina, Andrea;Morello, Francesca;Ferraris, Nicoletta;Corso, Simona;Penachioni, Junia;Giordano, Silvia;Tamagnone, Luca;Fasolo, Aldo
通讯作者：
Fasolo, Aldo
影响因子：
--
作者：
Fazzari P;Penachioni J;Gianola S;Rossi F;Eickholt BJ;Maina F;Alexopoulou L;Sottile A;Comoglio PM;Flavell RA;Tamagnone L
通讯作者：
Tamagnone L
影响因子：
5.3
作者：
Basile, JR;Afkhami, T;Gutkind, JS
通讯作者：
Gutkind, JS
影响因子：
2.7
作者：
Rodriguez, I;Araki, K;Vassalli, P
通讯作者：
Vassalli, P