The process that partitions the nascent vertebrate central nervous system into forebrain, midbrain, hindbrain, and spinal cord after neural induction is of fundamental interest in developmental biology, and is known to be dependent on Wnt/β-catenin signaling at multiple steps. Neural induction specifies neural ectoderm with forebrain character that is subsequently posteriorized by graded Wnt signaling: embryological and mutant analyses have shown that progressively higher levels of Wnt signaling induce progressively more posterior fates. However, the mechanistic link between Wnt signaling and the molecular subdivision of the neural ectoderm into distinct domains in the anteroposterior (AP) axis is still not clear. To better understand how Wnt mediates neural AP patterning, we performed a temporal dissection of neural patterning in response to manipulations of Wnt signaling in zebrafish. We show that Wnt-mediated neural patterning in zebrafish can be divided into three phases: (I) a primary AP patterning phase, which occurs during gastrulation, (II) a mes/r1 (mesencephalon-rhombomere 1) specification and refinement phase, which occurs immediately after gastrulation, and (III) a midbrain-hindbrain boundary (MHB) morphogenesis phase, which occurs during segmentation stages. A major outcome of these Wnt signaling phases is the specification of the major compartment divisions of the developing brain: first the MHB, then the diencephalic-mesencephalic boundary (DMB). The specification of these lineage divisions depends upon the dynamic changes of gene transcription in response to Wnt signaling, which we show primarily involves transcriptional repression or indirect activation. We show that otx2b is directly repressed by Wnt signaling during primary AP patterning, but becomes resistant to Wnt-mediated repression during late gastrulation. Also during late gastrulation, Wnt signaling becomes both necessary and sufficient for expression of wnt8b, en2a, and her5 in mes/r1. We suggest that the change in otx2b response to Wnt regulation enables a transition to the mes/r1 phase of Wnt-mediated patterning, as it ensures that Wnts expressed in the midbrain and MHB do not suppress midbrain identity, and consequently reinforce formation of the DMB. These findings integrate important temporal elements into our spatial understanding of Wnt-mediated neural patterning and may serve as an important basis for a better understanding of neural patterning defects that have implications in human health.

中文翻译：

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Wnt信号调节动态转录输出在不同的时间阶段的神经板模式。

在神经诱导后将新生的脊椎动物中枢神经系统分为前脑，中脑，后脑和脊髓的过程是发育生物学的基本兴趣，并且已知在多个步骤中依赖于Wnt /β-catenin信号传导。神经诱导指定具有前脑特征的神经外胚层，随后通过分级的Wnt信号传导将其后继化：胚胎学和突变分析表明，逐渐升高的Wnt信号传导水平诱导了更多的后代命运。但是，Wnt信号和神经外胚层的分子细分成前后（AP）轴的不同域之间的机制联系仍然不清楚。为了更好地了解Wnt如何介导神经AP模式，我们对斑马鱼中Wnt信号的操纵进行了神经模式的暂时解剖。我们显示斑马鱼中Wnt介导的神经模式可分为三个阶段：（I）在胃泌乳过程中发生的主要AP模式阶段，（II）mes / r1（中脑-菱形1）规范和完善阶段，其中发生在胃造瘘后立即发生，以及（III）在分割阶段发生的中脑-后脑边界（MHB）形态发生阶段。这些Wnt信号传递阶段的主要结果是发育中的大脑的主要区室划分的规范：首先是MHB，然后是二脑-中脑边界（DMB）。这些谱系划分的规范取决于基因转录响应Wnt信号的动态变化，我们展示的主要涉及转录抑制或间接激活。我们显示otx2b在主要AP模式期间被Wnt信号直接抑制，但在后期胃泌尿过程中变得对Wnt介导的抑制产生抗性。同样，在晚期胃形成过程中，Wnt信号转导对于在mes / r1中表达wnt8b，en2a和her5既必要又充分。我们建议，对Wnt调控的otx2b响应变化能够过渡到Wnt介导的模式的mes / r1阶段，因为它确保了在中脑和MHB中表达的Wnt不会抑制中脑的身份，从而加强了DMB的形成。 。