Yao Li-Chin, Blitz Ira L, Peiffer Daniel A, Phin Sopheap, Wang Ying, Ogata Souichi, Cho Ken W Y, Arora Kavita, Warrior Rahul
Department of Developmental and Cell Biology, and the Developmental Biology Center, University of California Irvine, Irvine, CA 92697, USA.
Development. 2006 Oct;133(20):4025-34. doi: 10.1242/dev.02561.
Bone Morphogenetic Proteins (Bmps) are secreted growth factors that play crucial roles in animal development across the phylogenetic spectrum. Bmp signaling results in the phosphorylation and nuclear translocation of Smads, downstream signal transducers that bind DNA. In Drosophila, the zinc finger protein Schnurri (Shn) plays a key role in signaling by the Bmp2/Bmp4 homolog Decapentaplegic (Dpp), by forming a Shn/Smad repression complex on defined promoter elements in the brinker (brk) gene. Brk is a transcriptional repressor that downregulates Dpp target genes. Thus, brk inhibition by Shn results in the upregulation of Dpp-responsive genes. We present evidence that vertebrate Shn homologs can also mediate Bmp responsiveness through a mechanism similar to Drosophila Shn. We find that a Bmp response element (BRE) from the Xenopus Vent2 promoter drives Dpp-dependent expression in Drosophila. However, in sharp contrast to its activating role in vertebrates, the frog BRE mediates repression in Drosophila. Remarkably, despite these opposite transcriptional polarities, sequence changes that abolish cis-element activity in Drosophila also affect BRE function in Xenopus. These similar cis requirements reflect conservation of trans-acting factors, as human Shn1 (hShn1; HIVEP1) can interact with Smad1/Smad4 and assemble an hShn1/Smad complex on the BRE. Furthermore, both Shn and hShn1 activate the BRE in Xenopus embryos, and both repress brk and rescue embryonic patterning defects in shn mutants. Our results suggest that vertebrate Shn proteins function in Bmp signal transduction, and that Shn proteins recruit coactivators and co-repressors in a context-dependent manner, rather than acting as dedicated activators or repressors.
骨形态发生蛋白（Bmps）是分泌型生长因子，在整个系统发育谱系的动物发育中发挥关键作用。Bmp信号传导导致Smads的磷酸化和核转位，Smads是结合DNA的下游信号转导分子。在果蝇中，锌指蛋白Schnurri（Shn）通过在brinker（brk）基因的特定启动子元件上形成Shn/Smad抑制复合物，在Bmp2/Bmp4同源物Decapentaplegic（Dpp）的信号传导中起关键作用。Brk是一种转录抑制因子，可下调Dpp靶基因。因此，Shn对brk的抑制导致Dpp反应性基因的上调。我们提供的证据表明，脊椎动物的Shn同源物也可以通过类似于果蝇Shn的机制介导Bmp反应性。我们发现，来自非洲爪蟾Vent2启动子的Bmp反应元件（BRE）在果蝇中驱动Dpp依赖性表达。然而，与其在脊椎动物中的激活作用形成鲜明对比的是，青蛙BRE在果蝇中介导抑制作用。值得注意的是，尽管存在这些相反的转录极性，但消除果蝇中顺式元件活性的序列变化也会影响非洲爪蟾中BRE的功能。这些相似的顺式要求反映了反式作用因子的保守性，因为人类Shn1（hShn1；HIVEP1）可以与Smad1/Smad4相互作用，并在BRE上组装hShn1/Smad复合物。此外，Shn和hShn1都能激活非洲爪蟾胚胎中的BRE，并且都能抑制brk并挽救shn突变体中的胚胎模式缺陷。我们的结果表明，脊椎动物的Shn蛋白在Bmp信号转导中起作用，并且Shn蛋白以依赖于上下文的方式募集共激活因子和共抑制因子，而不是作为专门的激活因子或抑制因子发挥作用。
