CDC42 is required for epicardial and pro-epicardial development by mediating FGF receptor trafficking to the plasma membrane

Jingjing Li, Lianjie Miao, Chen Zhao, Wasay Mohiuddin Shaikh Qureshi, David Shieh, Hua Guo, Yangyang Lu, Saiyang Hu, Alice Huang, Lu Zhang, Chen Leng Cai, Leo Q. Wan, Hongbo Xin, Peter Vincent, Harold A. Singer, Yi Zheng, Ondine Cleaver, Zhen Chuan Fan, Mingfu Wu

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The epicardium contributes to multiple cardiac lineages and is essential for cardiac development and regeneration. However, the mechanism of epicardium formation is unclear. This study aimed to establish the cellular and molecular mechanisms underlying the dissociation of pro-epicardial cells (PECs) from the pro-epicardium (PE) and their subsequent translocation to the heart to form the epicardium. We used lineage tracing, conditional deletion, mosaic analysis and ligand stimulation in mice to determine that both villous protrusions and floating cysts contribute to PEC translocation to myocardium in a CDC42-dependent manner. We resolved a controversy by demonstrating that physical contact of the PE with the myocardium constitutes a third mechanism for PEC translocation to myocardium, and observed a fourth mechanism in which PECs migrate along the surface of the inflow tract to reach the ventricles. Epicardial-specific Cdc42 deletion disrupted epicardium formation, and Cdc42 null PECs proliferated less, lost polarity and failed to form villous protrusions and floating cysts. FGF signaling promotes epicardium formation in vivo, and biochemical studies demonstrated that CDC42 is involved in the trafficking of FGF receptors to the cell membrane to regulate epicardium formation.

Original languageEnglish (US)
Pages (from-to)1635-1647
Number of pages13
JournalDevelopment (Cambridge)
Volume144
Issue number9
DOIs
StatePublished - May 1 2017

Keywords

  • CDC42
  • Epicardium development
  • FGF2 signaling
  • FGFR1 trafficking
  • Mouse
  • Pro-epicardial cells

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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  • Cite this

    Li, J., Miao, L., Zhao, C., Qureshi, W. M. S., Shieh, D., Guo, H., Lu, Y., Hu, S., Huang, A., Zhang, L., Cai, C. L., Wan, L. Q., Xin, H., Vincent, P., Singer, H. A., Zheng, Y., Cleaver, O., Fan, Z. C., & Wu, M. (2017). CDC42 is required for epicardial and pro-epicardial development by mediating FGF receptor trafficking to the plasma membrane. Development (Cambridge), 144(9), 1635-1647. https://doi.org/10.1242/dev.147173