Wt1 is Required for Cardiovascular Progenitor Cell Formation Through Transcriptional Control of Snail and E-cadherin

Overview

Journal Nat Genet

Specialty Genetics

Date 2009 Dec 22

PMID 20023660

Citations 181

Authors

Ofelia M Martinez-Estrada

Laura A Lettice

Abdelkader Essafi

Juan Antonio Guadix

Joan Slight

Victor Velecela

Emma Hall

Judith Reichmann

Paul S Devenney

Peter Hohenstein

Naoki Hosen

Robert E Hill

Ramon Munoz-Chapuli

Nicholas D Hastie

Affiliations

Soon will be listed here.

Abstract

The epicardial epithelial-mesenchymal transition (EMT) is hypothesized to generate cardiovascular progenitor cells that differentiate into various cell types, including coronary smooth muscle and endothelial cells, perivascular and cardiac interstitial fibroblasts and cardiomyocytes. Here we show that an epicardial-specific knockout of the gene encoding Wilms' tumor-1 (Wt1) leads to a reduction in mesenchymal progenitor cells and their derivatives. We show that Wt1 is essential for repression of the epithelial phenotype in epicardial cells and during embryonic stem cell differentiation through direct transcriptional regulation of the genes encoding Snail (Snai1) and E-cadherin (Cdh1), two of the major mediators of EMT. Some mesodermal lineages do not form in Wt1-null embryoid bodies, but this effect is rescued by the expression of Snai1, underscoring the importance of EMT in generating these differentiated cells. These new insights into the molecular mechanisms regulating cardiovascular progenitor cells and EMT will shed light on the pathogenesis of heart diseases and may help the development of cell-based therapies.

Citing Articles

Mesenchymal retinoic acid signaling is required for normal diaphragm development in mice.

Garcia Rivas J, Applin N, Albrechtsen J, Ghazanfari A, Doschak M, Clugston R FASEB J. 2025; 39(3):e70381.

PMID: 39921473 PMC: 11806406. DOI: 10.1096/fj.202402182R.

The Wilms' Tumor Suppressor WT1 in Cardiomyocytes: Implications for Cardiac Homeostasis and Repair.

Diaz Del Moral S, Wagner N, Wagner K Cells. 2025; 13(24.

PMID: 39768169 PMC: 11674098. DOI: 10.3390/cells13242078.

Mef2c- and Nkx2-5-Divergent Transcriptional Regulation of Chick WT1_76127 and Mouse Gm14014 lncRNAs and Their Implication in Epicardial Cell Migration.

Cano-Carrillo S, Garcia-Padilla C, Aranega A, Lozano-Velasco E, Franco D Int J Mol Sci. 2024; 25(23).

PMID: 39684625 PMC: 11640978. DOI: 10.3390/ijms252312904.

Immunotherapy Applications for Thymine Dimers and WT1 Antigen in Renal Cancers: A Comparative Statistical Analysis.

Latcu S, Bardan R, Cumpanas A, Barbos V, Baderca F, Gaje P J Pers Med. 2024; 14(6).

PMID: 38929778 PMC: 11205122. DOI: 10.3390/jpm14060557.

Epicardium and Coronary Vessels.

Ruiz-Villalba A, Guadix J, Perez-Pomares J Adv Exp Med Biol. 2024; 1441:155-166.

PMID: 38884710 DOI: 10.1007/978-3-031-44087-8_8.

References

Miyoshi Y, Ando A, Egawa C, Taguchi T, Tamaki Y, Tamaki H . High expression of Wilms' tumor suppressor gene predicts poor prognosis in breast cancer patients. Clin Cancer Res. 2002; 8(5):1167-71. View

Hohenstein P, Hastie N . The many facets of the Wilms' tumour gene, WT1. Hum Mol Genet. 2006; 15 Spec No 2:R196-201. DOI: 10.1093/hmg/ddl196. View

Franci C, Takkunen M, Dave N, Alameda F, Gomez S, Rodriguez R . Expression of Snail protein in tumor-stroma interface. Oncogene. 2006; 25(37):5134-44. DOI: 10.1038/sj.onc.1209519. View

Wagner N, Wagner K, Theres H, Englert C, Schedl A, Scholz H . Coronary vessel development requires activation of the TrkB neurotrophin receptor by the Wilms' tumor transcription factor Wt1. Genes Dev. 2005; 19(21):2631-42. PMC: 1276736. DOI: 10.1101/gad.346405. View

Nieto M . The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 2002; 3(3):155-66. DOI: 10.1038/nrm757. View

Spencer H, Eastham A, Merry C, Southgate T, Perez-Campo F, Soncin F . E-cadherin inhibits cell surface localization of the pro-migratory 5T4 oncofetal antigen in mouse embryonic stem cells. Mol Biol Cell. 2007; 18(8):2838-51. PMC: 1949355. DOI: 10.1091/mbc.e06-09-0875. View

Jat P, Noble M, Ataliotis P, Tanaka Y, Yannoutsos N, Larsen L . Direct derivation of conditionally immortal cell lines from an H-2Kb-tsA58 transgenic mouse. Proc Natl Acad Sci U S A. 1991; 88(12):5096-100. PMC: 51818. DOI: 10.1073/pnas.88.12.5096. View

Wagner K, Wagner N, Bondke A, Nafz B, Flemming B, Theres H . The Wilms' tumor suppressor Wt1 is expressed in the coronary vasculature after myocardial infarction. FASEB J. 2002; 16(9):1117-9. DOI: 10.1096/fj.01-0986fje. View

Merki E, Zamora M, Raya A, Kawakami Y, Wang J, Zhang X . Epicardial retinoid X receptor alpha is required for myocardial growth and coronary artery formation. Proc Natl Acad Sci U S A. 2005; 102(51):18455-60. PMC: 1317903. DOI: 10.1073/pnas.0504343102. View

10.

Mitiku N, Baker J . Genomic analysis of gastrulation and organogenesis in the mouse. Dev Cell. 2007; 13(6):897-907. DOI: 10.1016/j.devcel.2007.10.004. View

11.

Wessels A, Perez-Pomares J . The epicardium and epicardially derived cells (EPDCs) as cardiac stem cells. Anat Rec A Discov Mol Cell Evol Biol. 2003; 276(1):43-57. DOI: 10.1002/ar.a.10129. View

12.

Hosono S, Gross I, English M, Hajra K, Fearon E, Licht J . E-cadherin is a WT1 target gene. J Biol Chem. 2001; 275(15):10943-53. DOI: 10.1074/jbc.275.15.10943. View

13.

Keller G . Embryonic stem cell differentiation: emergence of a new era in biology and medicine. Genes Dev. 2005; 19(10):1129-55. DOI: 10.1101/gad.1303605. View

14.

Hosen N, Shirakata T, Nishida S, Yanagihara M, Tsuboi A, Kawakami M . The Wilms' tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis. Leukemia. 2007; 21(8):1783-91. DOI: 10.1038/sj.leu.2404752. View

15.

Mani S, Guo W, Liao M, Eaton E, Ayyanan A, Zhou A . The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008; 133(4):704-15. PMC: 2728032. DOI: 10.1016/j.cell.2008.03.027. View

16.

Blanco M, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J . Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene. 2002; 21(20):3241-6. DOI: 10.1038/sj.onc.1205416. View

17.

Moore A, McInnes L, Kreidberg J, Hastie N, Schedl A . YAC complementation shows a requirement for Wt1 in the development of epicardium, adrenal gland and throughout nephrogenesis. Development. 1999; 126(9):1845-57. DOI: 10.1242/dev.126.9.1845. View

18.

Spraggon L, Dudnakova T, Slight J, Lustig-Yariv O, Cotterell J, Hastie N . hnRNP-U directly interacts with WT1 and modulates WT1 transcriptional activation. Oncogene. 2006; 26(10):1484-91. DOI: 10.1038/sj.onc.1209922. View

19.

Nishikawa S, Jakt L, Era T . Embryonic stem-cell culture as a tool for developmental cell biology. Nat Rev Mol Cell Biol. 2007; 8(6):502-7. DOI: 10.1038/nrm2189. View

20.

Liu P, Jenkins N, Copeland N . A highly efficient recombineering-based method for generating conditional knockout mutations. Genome Res. 2003; 13(3):476-84. PMC: 430283. DOI: 10.1101/gr.749203. View