Foxn4 promotes gene expression required for the formation of multiple motile cilia
Foxn4 promotes gene expression required for the formation of multiple motile cilia
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DOI：
10.1242/dev.143859
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发表时间：
2016-12-15
期刊：
影响因子：
4.6
通讯作者：
Kintner, Chris
中科院分区：
文献类型：
--
作者：
Campbell, Evan P.;Quigley, Ian K.;Kintner, Chris
多纤毛细胞（Multiciliated cell， MCC）的分化涉及广泛的细胞器生物发生，需要扩展数百个活动纤毛。已知驱动这种细胞器生物发生所需的基因表达的关键转录调节因子由相关的卷曲蛋白Multicilin和gem1激活。本研究发现foxn4是非洲爪蟾皮肤MCC分化所需的一个新的下游靶点。当爪蟾胚胎中的Foxn4活性被抑制时，mcc表现出与Foxj1突变体相似的短暂纤毛发育缺陷，Foxj1是一种已知的运动调节所需基因的关键调节因子。RNAseq分析表明，Foxn4对部分Foxj1靶基因的共激活作用较强，而对许多Foxj1靶基因的共激活作用较弱。ChIPseq表明，尽管Foxn4和Foxj1经常在远端增强子上结合不同的靶标，但它们主要在MCC基因启动子上结合在一起。与这种共同调节一致，在foxn4和foxj1双突变体中，mcc的纤毛延伸比单突变体更严重。与Foxj1相比，Foxn4不需要通过参与左右模式的细胞来延长单个运动纤毛。这些结果表明，在MCC分化过程中，Foxn4在转录上对Foxj1进行了补充，从而形成了及时和完整的多运动纤毛生物发生所需的基因表达水平。
Multiciliated cell (MCC) differentiation involves extensive organelle biogenesis required to extend hundreds of motile cilia. Key transcriptional regulators known to drive the gene expression required for this organelle biogenesis are activated by the related coiled-coil proteins Multicilin and Gemc1. Here we identify foxn4 as a new downstream target of Multicilin required for MCC differentiation in Xenopus skin. When Foxn4 activity is inhibited in Xenopus embryos, MCCs show transient ciliogenesis defects similar to those seen in mutants of Foxj1, a known key regulator of genes required for motile ciliation. RNAseq analysis indicates that Foxn4 co-activates some Foxj1 target genes strongly and many Foxj1 targets weakly. ChIPseq suggests that whereas Foxn4 and Foxj1 frequently bind to different targets at distal enhancers, they largely bind together at MCC gene promoters. Consistent with this co-regulation, cilia extension by MCCs is more severely compromised in foxn4 and foxj1 double mutants than in single mutants. In contrast to Foxj1, Foxn4 is not required to extend a single motile cilium by cells involved in left-right patterning. These results indicate that Foxn4 complements Foxj1 transcriptionally during MCC differentiation, thereby shaping the levels of gene expression required for the timely and complete biogenesis of multiple motile cilia.