State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, 7 Donghu South Road, Wuhan 430072, China; University of the Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, 7 Donghu South Road, Wuhan 430072, China.
J Biol Chem. 2014 Mar 7;289(10):6604-6618. doi: 10.1074/jbc.M114.549758. Epub 2014 Jan 31.
Bone morphogenetic proteins (BMPs) are multifunctional growth factors that play crucial roles during embryonic development and cell fate determination. Nuclear transduction of BMP signals requires the receptor type Smad proteins, Smad1, Smad5, and Smad9. However, how these Smad proteins cooperate in vivo to regulate various developmental processes is largely unknown. In zebrafish, it was widely believed that the maternally expressed smad5 is essential for dorso-ventral (DV) patterning, and the zygotically transcribed smad1 is not required for normal DV axis establishment. In the present study, we have identified zygotically expressed smad9, which cooperates with smad1 downstream of smad5, to mediate zebrafish early DV patterning in a functional redundant manner. Although knockdown of smad1 or smad9 alone does not lead to visible dorsalization, double knockdown strongly dorsalizes zebrafish embryos, which cannot be efficiently rescued by smad5 overexpression, whereas the dorsalization induced by smad5 knockdown can be fully rescued by overexpression of smad1 or smad9. We have further revealed that the transcription initiations of smad1 and smad9 are repressed by each other, that they are direct transcriptional targets of Smad5, and that smad9, like smad1, is required for myelopoiesis. In conclusion, our study uncovers that smad1 and smad9 act redundantly to each other downstream of smad5 to mediate ventral specification and to regulate embryonic myelopoiesis.
骨形态发生蛋白（BMPs）是多功能生长因子，在胚胎发育和细胞命运决定中起着至关重要的作用。BMP 信号的核转导需要受体型 Smad 蛋白，Smad1、Smad5 和 Smad9。然而，这些 Smad 蛋白在体内如何合作来调节各种发育过程在很大程度上是未知的。在斑马鱼中，人们普遍认为母源性表达的 smad5 对于背腹（DV）模式形成是必不可少的，而合子转录的 smad1 对于正常的 DV 轴建立不是必需的。在本研究中，我们鉴定了合子表达的 smad9，它与 smad5 下游的 smad1 合作，以功能冗余的方式介导斑马鱼早期的 DV 模式形成。尽管单独敲低 smad1 或 smad9 不会导致明显的背化，但双敲低会强烈地使斑马鱼胚胎背化，这不能被 smad5 的过表达有效挽救，而 smad5 敲低诱导的背化可以被 smad1 或 smad9 的过表达完全挽救。我们进一步揭示了 smad1 和 smad9 的转录起始被彼此抑制，它们是 Smad5 的直接转录靶标，并且像 smad1 一样，smad9 也需要髓样细胞生成。总之，我们的研究揭示了 smad1 和 smad9 在 smad5 下游相互冗余地作用，介导腹侧特化，并调节胚胎髓样细胞生成。
