Top

Clinical and Translational Medicine

Published in:

Open Access 01-12-2017 | Short report

Deletion of Cdc42 in embryonic cardiomyocytes results in right ventricle hypoplasia

Authors: Yang Liu, Jian Wang, Jieli Li, Rui Wang, Binu Tharakan, Shenyuan L. Zhang, Carl W. Tong, Xu Peng

Published in: Clinical and Translational Medicine | Issue 1/2017

Abstract

Background

Cdc42 is a member of the Rho GTPase family and functions as a molecular switch in regulating cytoskeleton remodeling and cell polarity establishment. Inactivating Cdc42 in cardiomyocytes resulted in embryonic lethality with heart developmental defects, including ventricular septum defects and thin ventricle wall syndrome.

Findings

In this study, we have generated a Cdc42 cardiomyocyte knockout mouse line by crossing Cdc42/flox mice with myosin light chain 2a (MLC2a)-Cre mice. We found that the deletion of Cdc42 in embryonic cardiomyocytes resulted in an underdeveloped right ventricle. Microarray analysis and real-time PCR data analysis displayed that the deletion of Cdc42 decreased dHand expression level. In addition, we found evaginations in the ventricle walls of Cdc42 knockout hearts.

Conclusion

We concluded that Cdc42 plays an essential role in right ventricle growth.

Hoffman JI, Kaplan S (2002) The incidence of congenital heart disease. J Am Coll Cardiol 39(12):1890–1900CrossRefPubMed

Reller MD, Strickland MJ, Riehle-Colarusso T, Mahle WT, Correa A (2008) Prevalence of congenital heart defects in metropolitan Atlanta, 1998–2005. J Pediatr 153(6):807–813CrossRefPubMedPubMedCentral

Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R et al (2017) Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation 135(10):e146–e603CrossRefPubMedPubMedCentral

Bruneau BG (2008) The developmental genetics of congenital heart disease. Nature 451(7181):943–948CrossRefPubMed

Rochais F, Mesbah K, Kelly RG (2009) Signaling pathways controlling second heart field development. Circ Res 104(8):933–942CrossRefPubMed

Srivastava D (2006) Making or breaking the heart: from lineage determination to morphogenesis. Cell 126(6):1037–1148CrossRefPubMed

Farrell MJ, Kirby ML (2001) Cell biology of cardiac development. Int Rev Cytol 202:99–158CrossRefPubMed

Moon A (2008) Mouse models of congenital cardiovascular disease. Curr Top Dev Biol 84:171–248CrossRefPubMed

Bruneau BG (2013) Signaling and transcriptional networks in heart development and regeneration. Cold Spring Harb Perspect Biol 5(3):a008292CrossRefPubMedPubMedCentral

10.

Dib C, Araoz PA, Davies NP, Dearani JA, Ammash NM (2012) Hypoplastic right-heart syndrome presenting as multiple miscarriages. Tex Heart Inst J 39(2):249–254PubMedPubMedCentral

11.

Dimopoulos A, Sicko RJ, Kay DM, Rigler SL, Druschel CM, Caggana M et al (2017) Rare copy number variants in a population-based investigation of hypoplastic right heart syndrome. Birth Defects Res 109(1):8–15CrossRefPubMed

12.

Kelly RG, Brown NA, Buckingham ME (2001) The arterial pole of the mouse heart forms from Fgf10-expressing cells in pharyngeal mesoderm. Dev Cell 1(3):435–440CrossRefPubMed

13.

Waldo KL, Kumiski DH, Wallis KT, Stadt HA, Hutson MR, Platt DH et al (2001) Conotruncal myocardium arises from a secondary heart field. Development (Cambridge, England) 128(16):3179–3188

14.

Mjaatvedt CH, Nakaoka T, Moreno-Rodriguez R, Norris RA, Kern MJ, Eisenberg CA et al (2001) The outflow tract of the heart is recruited from a novel heart-forming field. Dev Biol 238(1):97–109CrossRefPubMed

15.

Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J et al (2003) Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5(6):877–889CrossRefPubMedPubMedCentral

16.

Srivastava D, Olson EN (2000) A genetic blueprint for cardiac development. Nature 407(6801):221–226CrossRefPubMed

17.

Lin Q, Srivastava D, Olson EN (1997) A transcriptional pathway for cardiac development. Cold Spring Harb Symp Quant Biol 62:405–411CrossRefPubMed

18.

Srivastava D, Thomas T, Lin Q, Kirby ML, Brown D, Olson EN (1997) Regulation of cardiac mesodermal and neural crest development by the bHLH transcription factor, dHAND. Nat Genet 16(2):154–160CrossRefPubMed

19.

Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420(6916):629–635CrossRefPubMed

20.

Cerione RA (2004) Cdc42: new roads to travel. Trends Cell Biol 14(3):127–132CrossRefPubMed

21.

Vogler G, Liu J, Iafe TW, Migh E, Mihaly J, Bodmer R (2014) Cdc42 and formin activity control non-muscle myosin dynamics during Drosophila heart morphogenesis. J Cell Biol 206(7):909–922CrossRefPubMedPubMedCentral

22.

Li J, Liu Y, Jin Y, Wang R, Wang J, Lu S et al (2017) Essential role of Cdc42 in cardiomyocyte proliferation and cell-cell adhesion during heart development. Dev Biol 421(2):271–283CrossRefPubMed

23.

Lage K, Greenway SC, Rosenfeld JA, Wakimoto H, Gorham JM, Segre AV et al (2012) Genetic and environmental risk factors in congenital heart disease functionally converge in protein networks driving heart development. Proc Natl Acad Sci USA 109(35):14035–14040CrossRefPubMedPubMedCentral

24.

Peng X, Wu X, Druso JE, Wei H, Park AY, Kraus MS et al (2008) Cardiac developmental defects and eccentric right ventricular hypertrophy in cardiomyocyte focal adhesion kinase (FAK) conditional knockout mice. Proc Natl Acad Sci USA 105(18):6638–6643CrossRefPubMedPubMedCentral

25.

McFadden DG, Barbosa AC, Richardson JA, Schneider MD, Srivastava D, Olson EN (2005) The Hand1 and Hand2 transcription factors regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner. Development (Cambridge, England) 132(1):189–201CrossRef

26.

Togi K, Kawamoto T, Yamauchi R, Yoshida Y, Kita T, Tanaka M (2004) Role of Hand1/eHAND in the dorso-ventral patterning and interventricular septum formation in the embryonic heart. Mol Cell Biol 24(11):4627–4635CrossRefPubMedPubMedCentral

27.

Low BC, Lim YP, Lim J, Wong ES, Guy GR (1999) Tyrosine phosphorylation of the Bcl-2-associated protein BNIP-2 by fibroblast growth factor receptor-1 prevents its binding to Cdc42GAP and Cdc42. J Biol Chem 274(46):33123–33130CrossRefPubMed

28.

Kaibuchi K, Kuroda S, Fukata M, Nakagawa M (1999) Regulation of cadherin-mediated cell-cell adhesion by the Rho family GTPases. Curr Opin Cell Biol 11(5):591–596CrossRefPubMed

Title: Deletion of Cdc42 in embryonic cardiomyocytes results in right ventricle hypoplasia
Authors: Yang Liu
Jian Wang
Jieli Li
Rui Wang
Binu Tharakan
Shenyuan L. Zhang
Carl W. Tong
Xu Peng
Publication date: 01-12-2017
Publisher: Springer Berlin Heidelberg
Published in: Clinical and Translational Medicine / Issue 1/2017
Electronic ISSN: 2001-1326
DOI: https://doi.org/10.1186/s40169-017-0171-4

At a glance: The STEP trials

Springer Medicine

Deletion of Cdc42 in embryonic cardiomyocytes results in right ventricle hypoplasia

Abstract

Background

Findings

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Findings

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2017

Translational research in pediatric pulmonary disease, 2017

CXCL9-11 polymorphisms are associated with liver fibrosis in patients with chronic hepatitis C: a cross-sectional study

Using single-cell multiple omics approaches to resolve tumor heterogeneity

Optimization of culture conditions for rapid clinical-scale expansion of human umbilical cord blood-derived mesenchymal stem cells

Post-zygotic genomic changes in glutamate and dopamine pathway genes may explain discordance of monozygotic twins for schizophrenia

Expression of Concern to: Evaluation of patients with multiple sclerosis using reverse nutech functional score and expanded disability status scale after human embryonic stem cell therapy