Prohibitin1 acts as a neural crest specifier in Xenopus development by repressing the transcription factor E2F1
Prohibitin1 acts as a neural crest specifier in Xenopus development by repressing the transcription factor E2F1
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DOI：
10.1242/dev.053405
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发表时间：
2010-12-01
期刊：
影响因子：
4.6
通讯作者：
Wedlich, Doris
中科院分区：
文献类型：
--
作者：
Schneider, Martina;Schambony, Alexandra;Wedlich, Doris
抑制素1（phb 1），最初被描述为细胞增殖的抑制剂，是一种在多个细胞区室中发现的高度保守的蛋白质。在细胞核中，它与转录调节因子Rb和E2 F1相互作用，控制细胞增殖和凋亡。在这里，我们解开了一个意想不到的新功能phb 1在非洲爪蟾颅神经嵴（CNC）的发展。Xphb 1是母系表达;合子表达的神经胚阶段成绩单积累在CNC和神经管。通过反义吗啉注射敲低Xphb 1导致foxD 3、snail 2和twist表达的丧失，而c-myc、AP-2和snail 1的表达保持不受影响。Xphb 2是其最接近的亲戚，不能取代Xphb 1，强调了Xphb 1功能的特异性。上位性分析将Xphb 1置于c-myc的下游和foxD 3、snail 2和twist的上游。为了阐明在Xphb 1的亚结构域所需的神经嵴基因调控，我们产生的缺失突变体，并测试他们的救援能力Xphb 1变形。E2 F1结合域被认为是必要的Xphb 1功能在神经嵴发育。获得和丧失功能的实验表明，Xphb 1抑制E2 F1的活动，通过Xphb 1抑制E2 F1是需要的扭曲，蜗牛2和foxD 3在CNC的表达。随着Xphb 1依赖c-myc下游的CNC说明符的子集，我们已经确定了一个新的分支点的神经嵴基因调控网络。
Prohibitin 1 (phb1), which was initially described as an inhibitor of cell proliferation, is a highly conserved protein found in multiple cellular compartments. In the nucleus it interacts with the transcriptional regulators Rb and E2F1 and controls cell proliferation and apoptosis. Here we unravel an unexpected novel function for phb1 in Xenopus cranial neural crest (CNC) development. Xphb1 is maternally expressed; zygotically expressed neurula stage transcripts accumulate in the CNC and the neural tube. Knockdown of Xphb1 by antisense morpholino injection results in the loss of foxD3, snail2 and twist expression, whereas expression of c-myc, AP-2 and snail1 remains unaffected. Xphb2, its closest relative, cannot substitute for Xphb1, underlining the specificity of Xphb1 function. Epistatic analyses place Xphb1 downstream of c-myc and upstream of foxD3, snail2 and twist. To elucidate which subdomain in Xphb1 is required for neural crest gene regulation we generated deletion mutants and tested their rescue ability in Xphb1 morphants. The E2F1-binding domain was found to be necessary for Xphb1 function in neural crest development. Gain-and loss-of-function experiments reveal that Xphb1 represses E2F1 activity; suppression of E2F1 through Xphb1 is required for twist, snail2 and foxD3 expression in the CNC. With the Xphb1 dependency of a subset of CNC specifiers downstream of c-myc, we have identified a new branching point in the neural crest gene regulatory network.