FOXF1 transcription factor promotes lung morphogenesis by inducing cellular proliferation in fetal lung mesenchyme.
FOXF1 transcription factor promotes lung morphogenesis by inducing cellular proliferation in fetal lung mesenchyme.
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DOI：
10.1016/j.ydbio.2018.08.011
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发表时间：
2018-11-01
影响因子：
2.7
通讯作者：
Kalinichenko VV
中科院分区：
文献类型：
--
作者：
Ustiyan V;Bolte C;Zhang Y;Han L;Xu Y;Yutzey KE;Zorn AM;Kalin TV;Shannon JM;Kalinichenko VV
器官发生受间充质-上皮信号事件的调控，这些信号事件诱导细胞类型的特定转录因子的表达，这些转录因子对细胞的增殖、分化和适当的组织模式至关重要。虽然间充质转录因子在间充质-上皮相互作用中起着关键作用，但横隔和内脏间充质中的转录网络仍然缺乏特征。Forkhead Box F1(FOXF1)转录因子在间充质细胞系中表达，但由于FOXF1−/−小鼠早期胚胎死亡，其在器官发生中的作用尚不清楚。在本研究中，我们建立了间充质特异性Foxf1基因敲除小鼠(−/−)，并证明了FoxF1对于呼吸、心血管和胃肠道器官系统的发育是必需的。由于心、肺、肝和食道的多种发育缺陷，从间充质中缺失Foxf1会导致胚胎在妊娠中期死亡。Foxf1基因缺失可抑制间充质细胞增殖和延迟分支肺形态发生。显微切割的远端肺间充质的基因表达谱和胎肺组织的芯片测序证实了FOXF1激活的多个靶基因，包括Wnt2、Wnt11、Wnt5A和Hoxb7。FOXF1通过直接转录抑制降低Wnt抑制因子Wif1的表达。此外，使用一个全局的FOXF1基因敲除小鼠品系(FOXF1−/−)，我们证明了FOXF1缺乏干扰了前肠组织外植体中肺芽的形成。最后，从平滑肌细胞谱系中缺失FOXF1(smMHC-Cre FOXF1−/−)会导致食道和气管过度伸展，气管和食管肌丢失，食道上皮错构化和平滑肌细胞增殖减少。综上所述，FOXF1通过调节肺间充质-上皮信号转导和刺激胎肺间充质细胞增殖来促进肺形态发生。
Organogenesis is regulated by mesenchymal-epithelial signaling events that induce expression of cell-type specific transcription factors critical for cellular proliferation, differentiation and appropriate tissue patterning. While mesenchymal transcription factors play a key role in mesenchymal-epithelial interactions, transcriptional networks in septum transversum and splanchnic mesenchyme remain poorly characterized. Forkhead Box F1 (FOXF1) transcription factor is expressed in mesenchymal cell lineages; however, its role in organogenesis remains uncharacterized due to early embryonic lethality of Foxf1−/− mice. In the present study, we generated mesenchyme-specific Foxf1 knockout mice (Dermol-Cre Foxf1−/−) and demonstrated that FOXF1 is required for development of respiratory, cardiovascular and gastrointestinal organ systems. Deletion of Foxf1 from mesenchyme caused embryonic lethality in the middle of gestation due to multiple developmental defects in the heart, lung, liver and esophagus. Deletion of Foxf1 inhibited mesenchyme proliferation and delayed branching lung morphogenesis. Gene expression profiling of micro-dissected distal lung mesenchyme and ChIP sequencing of fetal lung tissue identified multiple target genes activated by FOXF1, including Wnt2, Wnt11, Wnt5A and Hoxb7. FOXF1 decreased expression of the Wnt inhibitor Wif1 through direct transcriptional repression. Furthermore, using a global Foxf1 knockout mouse line (Foxf1−/−) we demonstrated that FOXF1-deficiency disrupts the formation of the lung bud in foregut tissue explants. Finally, deletion of Foxf1 from smooth muscle cell lineage (smMHC-Cre Foxf1−/−) caused hyper-extension of esophagus and trachea, loss of tracheal and esophageal muscle, mispatterning of esophageal epithelium and decreased proliferation of smooth muscle cells. Altogether, FOXF1 promotes lung morphogenesis by regulating mesenchymal-epithelial signaling and stimulating cellular proliferation in fetal lung mesenchyme.
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影响因子：
3.7
作者：
Bolte C;Zhang Y;Wang IC;Kalin TV;Molkentin JD;Kalinichenko VV
通讯作者：
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影响因子：
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