Gata4 regulates hedgehog signaling and Gata6 expression for outflow tract development

Jielin Liu, Henghui Cheng, Menglan Xiang, Lun Zhou, Bingruo Wu, Ivan P. Moskowitz, Ke Zhang, Linglin Xie

Research output: Contribution to journalArticle

Abstract

Dominant mutations of Gata4, an essential cardiogenic transcription factor (TF), were known to cause outflow tract (OFT) defects in both human and mouse, but the underlying molecular mechanism was not clear. In this study, Gata4 haploinsufficiency in mice was found to result in OFT defects including double outlet right ventricle (DORV) and ventricular septum defects (VSDs). Gata4 was shown to be required for Hedgehog (Hh)-receiving progenitors within the second heart field (SHF) for normal OFT alignment. Restored cell proliferation in the SHF by knocking-down Pten failed to rescue OFT defects, suggesting that additional cell events under Gata4 regulation is important. SHF Hh-receiving cells failed to migrate properly into the proximal OFT cushion, which is associated with abnormal EMT and cell proliferation in Gata4 haploinsufficiency. The genetic interaction of Hh signaling and Gata4 is further demonstrated to be important for OFT development. Gata4 and Smo double heterozygotes displayed more severe OFT abnormalities including persistent truncus arteriosus (PTA). Restoration of Hedgehog signaling renormalized SHF cell proliferation and migration, and rescued OFT defects in Gata4 haploinsufficiency. In addition, there was enhanced Gata6 expression in the SHF of the Gata4 heterozygotes. The Gata4-responsive repressive sites were identified within 1kbp upstream of the transcription start site of Gata6 by both ChIP-qPCR and luciferase reporter assay. These results suggested a SHF regulatory network comprising of Gata4, Gata6 and Hh-signaling for OFT development.

Original languageEnglish (US)
Article numbere1007711
JournalPLoS genetics
Volume15
Issue number5
DOIs
StatePublished - May 1 2019

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Hedgehogs
Erinaceidae
outflow
heart
Haploinsufficiency
defect
cell proliferation
Cell Proliferation
Heterozygote
heterozygosity
Persistent Truncus Arteriosus
Double Outlet Right Ventricle
Ventricular Septum
Transcription Initiation Site
mice
luciferase
Luciferases
cell movement
Cell Movement
Transcription Factors

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Liu, J., Cheng, H., Xiang, M., Zhou, L., Wu, B., Moskowitz, I. P., ... Xie, L. (2019). Gata4 regulates hedgehog signaling and Gata6 expression for outflow tract development. PLoS genetics, 15(5), [e1007711]. https://doi.org/10.1371/journal.pgen.1007711

Gata4 regulates hedgehog signaling and Gata6 expression for outflow tract development. / Liu, Jielin; Cheng, Henghui; Xiang, Menglan; Zhou, Lun; Wu, Bingruo; Moskowitz, Ivan P.; Zhang, Ke; Xie, Linglin.

In: PLoS genetics, Vol. 15, No. 5, e1007711, 01.05.2019.

Research output: Contribution to journalArticle

Liu, J, Cheng, H, Xiang, M, Zhou, L, Wu, B, Moskowitz, IP, Zhang, K & Xie, L 2019, 'Gata4 regulates hedgehog signaling and Gata6 expression for outflow tract development', PLoS genetics, vol. 15, no. 5, e1007711. https://doi.org/10.1371/journal.pgen.1007711
Liu, Jielin ; Cheng, Henghui ; Xiang, Menglan ; Zhou, Lun ; Wu, Bingruo ; Moskowitz, Ivan P. ; Zhang, Ke ; Xie, Linglin. / Gata4 regulates hedgehog signaling and Gata6 expression for outflow tract development. In: PLoS genetics. 2019 ; Vol. 15, No. 5.
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