Division of Molecular Embryology and Department of Theoretical Bioinformatics, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany.
Proc Natl Acad Sci U S A. 2011 Jun 21;108(25):10202-7. doi: 10.1073/pnas.1100179108. Epub 2011 Jun 1.
What makes embryogenesis a robust and canalized process is an important question in developmental biology. A bone morphogenetic protein (BMP) morphogen gradient plays a key role in embryonic development, and we are beginning to understand how the self-regulating properties of its signaling circuitry ensure robust embryonic patterning. An unexplored question is why the BMP signaling circuit is organized as a modular synexpression group, with a prevalence of feedback inhibitors. Here, we provide evidence from direct experimentation and mathematical modeling that the synexpressed feedback inhibitors BAMBI, SMAD6, and SMAD7 (i) expand the dynamic BMP signaling range essential for proper embryonic patterning and (ii) reduce interindividual phenotypic and molecular variability in Xenopus embryos. Thereby, negative feedback linearizes signaling responses and confers robust patterning, thus promoting canalized development. The presence of negative feedback inhibitors in other growth factor synexpression groups suggests that these properties may constitute a general principle.
胚胎发生为何是一个稳健且定型的过程，这是发育生物学中的一个重要问题。骨形态发生蛋白（BMP）形态发生素梯度在胚胎发育中起着关键作用，我们开始了解其信号转导电路的自调节特性如何确保胚胎模式的稳健性。一个尚未解决的问题是，为什么 BMP 信号通路被组织成一个模块化的共表达基因群，其中存在大量的反馈抑制剂。在这里，我们通过直接实验和数学建模提供了证据，表明共表达的反馈抑制剂 BAMBI、SMAD6 和 SMAD7（i）扩展了对正确胚胎模式形成至关重要的动态 BMP 信号范围，（ii）降低了爪蟾胚胎个体间表型和分子的可变性。因此，负反馈使信号反应线性化，并赋予稳健的模式形成，从而促进定型发育。其他生长因子共表达基因群中存在负反馈抑制剂表明，这些特性可能构成一个普遍原则。
