title: Specification of the mouse cardiac conduction system in the absence of Endothelin signaling.
abstract: Coordinated contraction of the heart is essential for survival and is regulated by the cardiac conduction system. Contraction of ventricular myocytes is controlled by the terminal part of the conduction system known as the Purkinje fiber network. Lineage analyses in chickens and mice have established that the Purkinje fibers of the peripheral ventricular conduction system arise from working myocytes during cardiac development. It has been proposed, based primarily on gain-of-function studies, that Endothelin signaling is responsible for myocyte-to-Purkinje fiber transdifferentiation during avian heart development. However, the role of Endothelin signaling in mammalian conduction system development is less clear, and the development of the cardiac conduction system in mice lacking Endothelin signaling has not been previously addressed. Here, we assessed the specification of the cardiac conduction system in mouse embryos lacking all Endothelin signaling. We found that mouse embryos that were homozygous null for both ednra and ednrb, the genes encoding the two Endothelin receptors in mice, were born at predicted Mendelian frequency and had normal specification of the cardiac conduction system and apparently normal electrocardiograms with normal QRS intervals. In addition, we found that ednra expression within the heart was restricted to the myocardium while ednrb expression in the heart was restricted to the endocardium and coronary endothelium. By establishing that ednra and ednrb are expressed in distinct compartments within the developing mammalian heart and that Endothelin signaling is dispensable for specification and function of the cardiac conduction system, this work has important implications for our understanding of mammalian cardiac development.
authors: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517, USA.
authors: Lisa L
authors: LL
authors: Hua
authors: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517, USA; Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158-2517, USA; Department of Medicine, University of California, San Francisco, CA 94158-2517, USA.
authors: Vasanth
authors: V
authors: Vedantham
authors: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517, USA.
authors: Ralston M
authors: RM
authors: Barnes
authors: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517, USA.
authors: Jianxin
authors: J
authors: Hu
authors: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517, USA.
authors: Ashley S
authors: AS
authors: Robinson
authors: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517, USA.
authors: Michael
authors: M
authors: Bressan
authors: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517, USA; Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158-2517, USA; Department of Pediatrics, University of California, San Francisco, CA 94158-2517, USA.
authors: Deepak
authors: D
authors: Srivastava
authors: Cardiovascular Research Institute, University of California, San Francisco, CA 94158-2517, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158-2517, USA. Electronic address: brian.black@ucsf.edu.
authors: Brian L
authors: BL
authors: Black
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D054338:Cell Transdifferentiation; D018031:Connexin 43 / Q000096:biosynthesis; D017630:Connexins / Q000096:biosynthesis; D004699:Endocardium / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D038081:Organogenesis; D011690:Purkinje Fibers / Q000196:embryology* / Q000502:physiology; D017466:Receptors, Endothelin / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction; D000097003:Gap Junction alpha-5 Protein
chemical_list: D018031:Connexin 43; D017630:Connexins; D016232:Endothelins; D017466:Receptors, Endothelin; D000097003:Gap Junction alpha-5 Protein; C543076:GJA1 protein, mouse
keywords: CCS-lacZ; Cardiac conduction system; ET(A); ET(B); Endothelin; Mouse; Purkinje fibers