State Key Laboratory of Biomembrane and Membrane Engineering, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Dev Cell. 2012 May 15;22(5):1065-78. doi: 10.1016/j.devcel.2012.03.001.
BMP signals play pivotal roles in dorsoventral patterning of vertebrate embryos. The role of Ppp4c, the catalytic subunit of ubiquitous protein phosphatase 4, in vertebrate embryonic development and underlying mechanisms is poorly understood. Here, we demonstrate that knockdown of zebrafish ppp4cb and/or ppp4ca inhibits ventral development in embryos and also blocks ventralizing activity of ectopic Smad5. Biochemical analyses reveal that Ppp4c is a direct binding partner and transcriptional coactivator of Smad1/Smad5. In response to BMP, Ppp4c is recruited to the Smad1-occupied promoter, and its phosphatase activity is essential in inhibiting HDAC3 activity and, consequently, potentiating transcriptional activation. Consistently, genetic or chemical interference of Hdac3 expression or activity compromises the dorsalizing phenotype induced by ppp4cb knockdown. We conclude that Ppp4c is a critical positive regulator of BMP/Smad signaling during embryonic dorsoventral pattern formation in zebrafish.
BMP 信号在脊椎动物胚胎的背腹模式形成中发挥关键作用。普遍存在的蛋白磷酸酶 4 的催化亚基 Ppp4c 在脊椎动物胚胎发育中的作用及其潜在机制知之甚少。在这里，我们证明了斑马鱼 ppp4cb 和/或 ppp4ca 的敲低抑制了胚胎的腹侧发育，并阻断了异位 Smad5 的腹侧化活性。生化分析表明，Ppp4c 是 Smad1/Smad5 的直接结合伴侣和转录共激活因子。响应 BMP，Ppp4c 被招募到 Smad1 占据的启动子上，其磷酸酶活性对于抑制 HDAC3 活性以及增强转录激活至关重要。一致地，Hdac3 表达或活性的遗传或化学干扰会损害由 ppp4cb 敲低诱导的背侧表型。我们得出结论，Ppp4c 是斑马鱼胚胎背腹模式形成过程中 BMP/Smad 信号的关键正调控因子。
