A homeodomain feedback circuit underlies step-function interpretation of a Shh morphogen gradient during ventral neural patterning
A homeodomain feedback circuit underlies step-function interpretation of a Shh morphogen gradient during ventral neural patterning
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DOI：
10.1242/dev.054288
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发表时间：
2010-12-01
期刊：
影响因子：
4.6
通讯作者：
Ericson, Johan
中科院分区：
文献类型：
--
作者：
Lek, Madelen;Dias, Jose M.;Ericson, Johan
形态学梯度的部署是建立生长组织中细胞多样性的核心策略，但是对于细胞外信号浓度的微小差异如何转化为响应细胞中稳健的图案输出。我们已经检查了同源域蛋白的活性，这些活性被认为是在神经模式中的分级SHH信号下游操作，并描述了SHH途径和同源域转录因子之间的反馈电路，从而建立了SHH信号活性的非级调控。 NKX2蛋白本质地增强了进料的扩增中的SHH反应，并且是腹板板和P3祖细胞命运所必需的。相反，PAX6具有拮抗SHH信号传导的相对函数，SHH信号传导对SHH响应提供了内在的抗性，并且对于约束随着时间的推移限制SHH梯度的电感能力很重要。我们的数据进一步表明，地板细胞和P3祖细胞的模式是通过神经元电位的时间开关而不是通过不同的SHH浓度进行的。这些数据表明，响应细胞的动态，非分数变化对于SHH形态学解释至关重要，并提供了一种理论来解释形态学暴露的细胞记忆现象。
The deployment of morphogen gradients is a core strategy to establish cell diversity in developing tissues, but little is known about how small differences in the concentration of extracellular signals are translated into robust patterning output in responding cells. We have examined the activity of homeodomain proteins, which are presumed to operate downstream of graded Shh signaling in neural patterning, and describe a feedback circuit between the Shh pathway and homeodomain transcription factors that establishes non-graded regulation of Shh signaling activity. Nkx2 proteins intrinsically strengthen Shh responses in a feed-forward amplification and are required for ventral floor plate and p3 progenitor fates. Conversely, Pax6 has an opposing function to antagonize Shh signaling, which provides intrinsic resistance to Shh responses and is important to constrain the inductive capacity of the Shh gradient over time. Our data further suggest that patterning of floor plate cells and p3 progenitors is gated by a temporal switch in neuronal potential, rather than by different Shh concentrations. These data establish that dynamic, non-graded changes in responding cells are essential for Shh morphogen interpretation, and provide a rationale to explain mechanistically the phenomenon of cellular memory of morphogen exposure.