The facial neural crest controls fore- and midbrain patterning by regulating Foxg1 expression through Smad1 activity
The facial neural crest controls fore- and midbrain patterning by regulating Foxg1 expression through Smad1 activity
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DOI：
10.1242/dev.101790
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发表时间：
2014-06-01
期刊：
影响因子：
4.6
通讯作者：
Creuzet, Sophie
中科院分区：
文献类型：
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作者：
Aguiar, Diego P.;Sghari, Soufien;Creuzet, Sophie
面神经脊(FNC)是一种形成头面部结构的多能胚胎结构，控制大脑组织者的活动并刺激大脑生长。为了了解FNC如何传递其营养效应，我们研究了Smad1在FOXG1调控中的作用。Smad1编码一个细胞内转导蛋白，多条信号通路汇聚到该转导蛋白上。FOXG1是端脑发育所必需的转录因子，其突变可导致小头畸形和智力低下。在迁移前的FNC细胞中进行基于RNA干扰(RNAi)的Smad1沉默。在RNAi分子电穿孔后不久，Smad1失活取消了FOXG1在雏鸡端脑中的表达，导致戏剧性的小头畸形和部分全前脑。此外，FOXG1活性缺失改变了双/中脑神经上皮细胞OTX2和Foxa2的表达。然而，当介导成纤维细胞生长因子和Wnt信号的突变形式的Smad1被导入FNC细胞时，这些缺陷被克服了。我们还表明，在Smad1活性的下游，FNC产生的Wnt拮抗剂Dkk1通过调节FOXG1活性启动了端脑的指定。此外，Cerberus在FNC来源的间充质细胞中的活性与Dkk1协同控制FOXG1的表达，并维持OTX2和Foxa2之间的平衡。
The facial neural crest (FNC), a pluripotent embryonic structure forming craniofacial structures, controls the activity of brain organisers and stimulates cerebrum growth. To understand how the FNC conveys its trophic effect, we have studied the role of Smad1, which encodes an intracellular transducer, to which multiple signalling pathways converge, in the regulation of Foxg1. Foxg1 is a transcription factor essential for telencephalic specification, the mutation of which leads to microcephaly and mental retardation. Smad1 silencing, based on RNA interference (RNAi), was performed in pre-migratory FNC cells. Soon after electroporation of RNAi molecules, Smad1 inactivation abolished the expression of Foxg1 in the chick telencephalon, resulting in dramatic microcephaly and partial holoprosencephaly. In addition, the depletion of Foxg1 activity altered the expression Otx2 and Foxa2 in di/mesencephalic neuroepithelium. However, when mutated forms of Smad1 mediating Fgf and Wnt signalling were transfected into FNC cells, these defects were overcome. We also show that, downstream of Smad1 activity, Dkk1, a Wnt antagonist produced by the FNC, initiated the specification of the telencephalon by regulating Foxg1 activity. Additionally, the activity of Cerberus in FNC-derived mesenchyme synergised with Dkk1 to control Foxg1 expression and maintain the balance between Otx2 and Foxa2.