title: Essential role of Cdc42 in cardiomyocyte proliferation and cell-cell adhesion during heart development.
abstract: Cdc42 is a member of the Rho GTPase family and functions as a molecular switch in regulating cell migration, proliferation, differentiation and survival. However, the role of Cdc42 in heart development remains largely unknown. To determine the function of Cdc42 in heart formation, we have generated a Cdc42 cardiomyocyte knockout (CCKO) mouse line by crossing Cdc42 flox mice with myosin light chain (MLC) 2a-Cre mice. The inactivation of Cdc42 in embryonic cardiomyocytes induced lethality after embryonic day 12.5. Histological analysis of CCKO embryos showed cardiac developmental defects that included thin ventricular walls and ventricular septum defects. Microarray and real-time PCR data also revealed that the expression level of p21 was significantly increased and cyclin B1 was dramatically decreased, suggesting that Cdc42 is required for cardiomyocyte proliferation. Phosphorylated Histone H3 staining confirmed that the inactivation of Cdc42 inhibited cardiomyocytes proliferation. In addition, transmission electron microscope studies showed disorganized sarcomere structure and disruption of cell-cell contact among cardiomyocytes in CCKO hearts. Accordingly, we found that the distribution of N-cadherin/β-Catenin in CCKO cardiomyocytes was impaired. Taken together, our data indicate that Cdc42 is essential for cardiomyocyte proliferation, sarcomere organization and cell-cell adhesion during heart development.
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University, USA.
authors.forename: Jieli
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University, USA.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University, USA; Department of Cardiology, Yangpu District Central Hospital, Tongji University, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: VanBuren
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Dostal
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University, USA. Electronic address: shenyuan.zhang@medicine.tamhsc.edu.
authors.forename: Shenyuan L
authors.initials: SL
authors.lastname: Zhang
authors.affiliation: Department of Medical Physiology, College of Medicine, Texas A&M University, USA. Electronic address: xpeng@medicine.tamhsc.edu.
authors.forename: Xu
authors.initials: X
authors.lastname: Peng
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D002450:Cell Communication; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D020964:Embryo Loss / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D006345:Heart Septal Defects, Ventricular / Q000196:embryology / Q000473:pathology; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D009928:Organ Specificity; D021381:Protein Transport; D051176:beta Catenin / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D051176:beta Catenin; D020764:cdc42 GTP-Binding Protein
keywords: Cardiomyocyte proliferation; Cdc42; Cell-cell adhesion; Heart development; Rho GTPase