Maternal Xenopus Zic2 negatively regulates nodal-related gene expression during anteroposterior patterning
Maternal Xenopus Zic2 negatively regulates nodal-related gene expression during anteroposterior patterning
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DOI：
10.1242/dev.02066
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发表时间：
2005-11-01
期刊：
影响因子：
4.6
通讯作者：
Wylie, C
中科院分区：
文献类型：
--
作者：
Houston, DW;Wylie, C
在非洲爪蟾的发展过程中，母亲的mRNA和蛋白质存储在鸡蛋直接早期图案的事件，如规格的背腹轴和初级胚层。在表达筛选，以确定母亲的因素，早期发展的重要性，我们分离出一个截短的cDNA为母体Zic 2（tZic 2），编码锌指转录因子。预测的tZic 2蛋白缺乏N-末端区域，但保留了锌指结构域。当在胚胎中表达时，tZic 2抑制头部和轴向发育，并阻断全长Zic 2诱导神经嵴基因的能力。使用反义寡核苷酸从卵母细胞中耗尽母体Zic 2，引起外原肠胚形成、前截断和轴向缺陷。我们发现，母亲Zic 2的损失的结果在持久和增加的表达非洲爪蟾神经相关（Xnr）基因，除了Xnr 4，和整体增加Nodal信号。注射Nodal拮抗剂Cerberus短，降低了Zic 2耗尽胚胎的头部和轴向缺陷的严重程度。Zic 2的耗尽不能恢复Xnr表达的胚胎额外耗尽VegT，T-结构域转录因子和Xnr基因转录的激活剂。两者合计，我们的研究结果表明，在早期发展的Xnr基因的抑制母体Zic 2的作用。ZIC 2在人类前脑无裂畸形（HPE）中发生突变，这是一种大脑半球分离的严重缺陷，这些结果加强了Nodal相关活动增加是HPE原因的建议。
During the development of Xenopus laevis, maternal mRNAs and proteins stored in the egg direct early patterning events such as the specification of the dorsoventral axis and primary germ layers. In an expression screen to identify maternal factors important for early development, we isolated a truncated cDNA for maternal Zic2 (tZic2), encoding a zinc-finger transcription factor. The predicted tZic2 protein lacked the N-terminal region, but retained the zinc-finger domain. When expressed in embryos, tZic2 inhibited head and axial development, and blocked the ability of full-length Zic2 to induce neural crest genes. Depletion of maternal Zic2 from oocytes, using antisense oligonucleotides, caused exogastrulation, anterior truncations and axial defects. We show that loss of maternal Zic2 results in persistent and increased expression of Xenopus nodal-related (Xnr) genes, except for Xnr4, and overall increased Nodal signaling. Injection of a Nodal antagonist, Cerberus-short, reduced the severity of head and axial defects in Zic2-depleted embryos. Depletion of Zic2 could not restore Xnr expression to embryos additionally depleted of VegT, a T-domain transcription factor and an activator of Xnr gene transcription. Taken together, our results suggest a role for maternal Zic2 in the suppression of Xnr genes in early development. ZIC2 is mutated in human holoprosencephaly (HPE), a severe defect in brain hemisphere separation, and these results strengthen the suggestion that increased Nodal-related activity is a cause of HPE.