Self-regulation of the head-inducing properties of the Spemann organizer
Self-regulation of the head-inducing properties of the Spemann organizer
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DOI：
10.1073/pnas.1203000109
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发表时间：
2012-09-18
影响因子：
11.1
通讯作者：
Piccolo, Stefano
中科院分区：
文献类型：
--
作者：
Inui, Masafumi;Montagner, Marco;Piccolo, Stefano
Spemann组织者因其广泛的模式效应而从胚胎的其他信号中心中脱颖而出。它主要通过分泌生长因子拮抗剂来定义沿脊椎动物体的前后轴和背腹轴发育。十多年前提出的定性模型解释了组织者的区域特异性诱导（即头部和躯干）是拮抗剂不同组合的结果。例如，头部诱导是通过细胞外抑制Wnt、BMP和Nodal配体介导的。然而，对于这些拮抗剂的水平如何与它们的靶标以及最初负责胚层和组织者形成的因子（包括Nodal本身）的水平协调一致，人们知之甚少。本研究表明，头部组织者发育的关键成分，即节点配体、节点拮抗剂和ADMP配体，通过一个由互锁反馈和前馈回路组成的自我调节网络，相互调节彼此的强度和活性范围。这种串扰的一个关键因素是ACVR2a的有限可用性，这是node和ADMP必须竞争的。通过在细胞外捕获Nodal， Nodal拮抗剂Cerberus和Lefty允许ADMP活性。系统自我调节是因为ADMP/ACVR2a/Smad1信号反过来抑制Nodal拮抗剂的表达，从而重新建立平衡。总而言之，这项工作揭示了一组前所未有的相互作用在组织者中运作，这对胚胎模式至关重要。
The Spemann organizer stands out from other signaling centers of the embryo because of its broad patterning effects. It defines development along the anteroposterior and dorsoventral axes of the vertebrate body, mainly by secreting antagonists of growth factors. Qualitative models proposed more than a decade ago explain the organizer's region-specific inductions (i.e., head and trunk) as the result of different combinations of antagonists. For example, head induction is mediated by extracellular inhibition of Wnt, BMP, and Nodal ligands. However, little is known about how the levels of these antagonists become harmonized with those of their targets and with the factors initially responsible for germ layers and organizer formation, including Nodal itself. Here we show that key ingredients of the head-organizer development, namely Nodal ligands, Nodal antagonists, and ADMP ligands reciprocally adjust each other's strength and range of activity by a self-regulating network of interlocked feedback and feedforward loops. A key element in this cross-talk is the limited availability of ACVR2a, for which Nodal and ADMP must compete. By trapping Nodal extracellularly, the Nodal antagonists Cerberus and Lefty are permissive for ADMP activity. The system self-regulates because ADMP/ACVR2a/Smad1 signaling in turn represses the expression of the Nodal antagonists, reestablishing the equilibrium. In sum, this work reveals an unprecedented set of interactions operating within the organizer that is critical for embryonic patterning.