O'Shaughnessy Ryan F L, Welti Jonathan C, Sully Katherine, Byrne Carolyn
Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, UK.
Development. 2009 Oct;136(20):3423-31. doi: 10.1242/dev.037010. Epub 2009 Sep 17.
Acquisition of epidermal barrier function occurs late in mouse gestation. Several days before birth a wave of barrier acquisition sweeps across murine fetal skin, converging on dorsal and ventral midlines. We investigated the molecular pathways active during epidermal barrier formation. Akt signaling increased as the barrier wave crossed epidermis and Jun was transiently dephosphorylated. Inhibitor experiments on embryonic explants showed that the dephosphorylation of Jun was dependent on both Akt and protein phosphatase 2A (Pp2a). Inhibition of Pp2a and Akt signaling also caused defects in epidermal barrier formation. These data are compatible with a model for developmental barrier acquisition mediated by Pp2a regulation of Jun dephosphorylation, downstream of Akt signaling. Support for this model was provided by siRNA-mediated knockdown of Ppp2r2a (Pr55alpha or B55alpha), a regulatory subunit of Pp2a expressed in an Akt-dependent manner in epidermis during barrier formation. Ppp2r2a reduction caused significant increase in Jun phosphorylation and interfered with the acquisition of barrier function, with barrier acquisition being restored by inhibition of Jun phosphorylation. Our data provide strong evidence that Ppp2r2a is a regulatory subunit of Pp2a that targets this phosphatase to Jun, and that Pp2a action is necessary for barrier formation. We therefore describe a novel Akt-dependent Pp2a activity that acts at least partly through Jun to affect initial barrier formation during late embryonic epidermal development.
小鼠妊娠后期表皮屏障功能开始形成。出生前几天，一股屏障形成浪潮席卷小鼠胎儿皮肤，汇聚于背侧和腹侧中线。我们研究了表皮屏障形成过程中活跃的分子途径。随着屏障波穿过表皮，Akt信号增强，Jun短暂去磷酸化。对胚胎外植体的抑制剂实验表明，Jun的去磷酸化依赖于Akt和蛋白磷酸酶2A（Pp2a）。抑制Pp2a和Akt信号也会导致表皮屏障形成缺陷。这些数据与一个模型相符，即由Pp2a对Jun去磷酸化的调控介导的发育性屏障形成模型，该模型在Akt信号下游。siRNA介导的Ppp2r2a（Pr55alpha或B55alpha）敲低为该模型提供了支持，Ppp2r2a是Pp2a的一个调节亚基，在屏障形成过程中以Akt依赖的方式在表皮中表达。Ppp2r2a的减少导致Jun磷酸化显著增加，并干扰屏障功能的获得，通过抑制Jun磷酸化可恢复屏障功能的获得。我们的数据提供了有力证据，表明Ppp2r2a是Pp2a的一个调节亚基，可将该磷酸酶靶向Jun，且Pp2a的作用对于屏障形成是必要的。因此，我们描述了一种新的Akt依赖的Pp2a活性，它至少部分通过Jun起作用，以影响胚胎后期表皮发育过程中的初始屏障形成。
