HESX1-and TCF3-mediated repression of Wnt/β-catenin targets is required for normal development of the anterior forebrain
HESX1-and TCF3-mediated repression of Wnt/β-catenin targets is required for normal development of the anterior forebrain
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DOI：
10.1242/dev.066597
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发表时间：
2011-11-15
期刊：
影响因子：
4.6
通讯作者：
Martinez-Barbera, Juan Pedro
中科院分区：
文献类型：
--
作者：
Andoniadou, Cynthia L.;Signore, Massimo;Martinez-Barbera, Juan Pedro
Wnt/β-连环蛋白通路在脊椎动物神经板的区域化过程中起着重要作用，并且其在最前部神经外胚层中的抑制是正常前脑发育所需的。Hesx 1是一种保守的脊椎动物特异性转录因子，在非洲爪蟾、小鼠和人类的前脑发育中是必需的。缺乏Hesx 1的小鼠胚胎表现出不同程度的前脑缺陷，但这些缺陷背后的分子机制尚未完全了解。在这里，我们表明，注射hesx 1吗啉到一个“敏感”合子无头（tcf 3）突变体的背景导致严重的前脑和眼睛的缺陷，这表明Hesx 1和Wnt通路之间的相互作用在斑马鱼前脑发育。与Wnt信号转导抑制的要求一致，我们强调了Hesx 1和Tcf 3（Wnt靶基因的转录抑制因子）之间的协同基因剂量依赖性相互作用，以维持小鼠胚胎发育过程中前前脑的身份。此外，我们发现，Tcf 3是必不可少的神经外胚层内，以保持前字符，它与Hesx 1的相互作用，确保Wnt目标的抑制在发展中的前脑。通过在小鼠中采用有条件的功能丧失方法，我们证明了β-连环蛋白的缺失，以及随之而来的Hesx 1缺陷胚胎发育中前脑的Wnt信号传导的减少，导致前脑缺陷的显著拯救。最后，从Hesx 1基因座表达eGFP的小鼠胚胎前前脑前体的转录谱提供了分子证据，支持Hesx 1在发育前脑中介导Wnt/β-连环蛋白靶激活抑制的新功能。
The Wnt/beta-catenin pathway plays an essential role during regionalisation of the vertebrate neural plate and its inhibition in the most anterior neural ectoderm is required for normal forebrain development. Hesx1 is a conserved vertebrate-specific transcription factor that is required for forebrain development in Xenopus, mice and humans. Mouse embryos deficient for Hesx1 exhibit a variable degree of forebrain defects, but the molecular mechanisms underlying these defects are not fully understood. Here, we show that injection of a hesx1 morpholino into a 'sensitised' zygotic headless (tcf3) mutant background leads to severe forebrain and eye defects, suggesting an interaction between Hesx1 and the Wnt pathway during zebrafish forebrain development. Consistent with a requirement for Wnt signalling repression, we highlight a synergistic gene dosage-dependent interaction between Hesx1 and Tcf3, a transcriptional repressor of Wnt target genes, to maintain anterior forebrain identity during mouse embryogenesis. In addition, we reveal that Tcf3 is essential within the neural ectoderm to maintain anterior character and that its interaction with Hesx1 ensures the repression of Wnt targets in the developing forebrain. By employing a conditional loss-of-function approach in mouse, we demonstrate that deletion of beta-catenin, and concomitant reduction of Wnt signalling in the developing anterior forebrain of Hesx1-deficient embryos, leads to a significant rescue of the forebrain defects. Finally, transcriptional profiling of anterior forebrain precursors from mouse embryos expressing eGFP from the Hesx1 locus provides molecular evidence supporting a novel function of Hesx1 in mediating repression of Wnt/beta-catenin target activation in the developing forebrain.