The amino-terminal region of Gli3 antagonizes the Shh response and acts in dorsoventral fate specification in the developing spinal cord
The amino-terminal region of Gli3 antagonizes the Shh response and acts in dorsoventral fate specification in the developing spinal cord
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DOI：
10.1016/s0012-1606(03)00065-4
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发表时间：
2003-05-15
影响因子：
2.7
通讯作者：
Roelink, H
中科院分区：
文献类型：
--
作者：
Meyer, NP;Roelink, H
Shh的浓度梯度被认为是形成腹侧神经管的模式，而这些腹侧细胞类型在Shh(-/-)小鼠中是不存在的。基于体外和遗传学研究，含锌指转录因子Gli 1、2和3是Shh细胞内反应的介体。在Gli1(-/-)；gli2(-/-)小鼠中没有底板和相邻细胞类型，但在Shh(-/-)；gli3(-/-)双突变体中神经管中的Shh(-/-)表型的部分减轻。这与Gli3作为Shh反应抑制因子的预测角色是一致的。Shh可阻断Gli3抑制物的活性。为了测试Gli3的阻遏形式在神经管中的作用，设计了一个截短版本的Gli3(Gli3R*)来模拟Pallister Hall等位基因。Gli3R*是一种不依赖Shh信号的结构性阻遏因子。Gli3R*在鸡神经管中的错误表达导致I类背侧祖细胞蛋白的腹侧扩张和II类腹侧祖细胞蛋白的丢失，这些蛋白与预期的Shh反应抑制因子的活性一致。BMP反应的激活足以维持神经板外植体中胶质3的表达，这可能是BMP拮抗Shh反应的机制之一。(C)2003年埃尔塞维尔科学公司(美国)。版权所有。
A concentration gradient of Shh is thought to pattern the ventral neural tube, and these ventral cell types are absent in shh(-/-) mice. Based on in vitro and genetic studies, the zinc finger-containing transcription factors Gli 1, 2, and 3 are mediators of the Shh intracellular response. The floorplate and adjacent cell types are absent in glil(-/-);gli2(-/-) mice, but part of the Shh(-/-) phenotype in the neural tube is alleviated in the Shh(-/-);gli3(-/-) double mutant. This is consistent with the predicted role of Gli3 as a repressor of the Shh response. Gli3 repressor activity is blocked by Shh. In order to test the role of the repressor form of Gli3 in the neural tube, a truncated version of Gli3 (Gli3R*) was designed to mimic a Pallister Hall allele. Gli3R* acts as a constitutive repressor independent of Shh signaling. Misexpression of Gli3R* in the chick neural tube caused a ventral expansion of class-I, dorsal progenitor proteins and a loss of class-II, ventral progenitor proteins consistent with expected activity as a repressor of the Shh response. Activation of the BMP response is sufficient to maintain gli3 expression in neural plate explants, which might be a mechanism by which BMPs antagonize the Shh response. (C) 2003 Elsevier Science (USA). All rights reserved.