title: Misexpression of Tbx18 in cardiac chambers of fetal mice interferes with chamber-specific developmental programs but does not induce a pacemaker-like gene signature.
abstract: Initiation of cardiac excitation depends on a specialized group of cardiomyocytes at the venous pole of the heart, the sinoatrial node (SAN). The T-box transcription factor gene Tbx18 is expressed in the SAN myocardium and is required for formation of a large portion of the pacemaker. Previous studies suggested that Tbx18 is also sufficient to reprogram ventricular cardiomyocytes into SAN cells in rat, guinea-pig and pig hearts. To evaluate the consequences of misexpression of Tbx18 for imposing a nodal phenotype onto chamber myocardial cells in fetal mice, we used two independent conditional approaches with chamber-specific cre driver lines and an Hprt(Tbx18) misexpression allele. Myh6-Cre/+;Hprt(Tbx18/y) mice developed dilated atria with thickened walls, reduced right ventricles and septal defects that resulted in reduced embryonic and post-natal survival. Tagln-Cre/+;Hprt(Tbx18/y) mice exhibited slightly smaller hearts with rounded trabeculae that supported normal embryonic survival. Molecular analyses showed that the SAN gap junction and ion channel profile was not ectopically induced in chamber myocardium but the working myocardial gene program was partially inhibited in atria and ventricles of both misexpression models. Left atrial expression of Pitx2 was strongly repressed in Myh6-Cre/+;Hprt(Tbx18/y) embryos. We conclude that exclusion of Tbx18 expression from the developing atria and (right) ventricle is important to achieve normal cardiac left-right patterning and myocardial differentiation, and that Tbx18 is not sufficient to induce full SAN differentiation of chamber cardiomyocytes in fetal mice.
authors.affiliation: Institut für Molekularbiologie, OE5250, Medizinische Hochschule Hannover, Carl-Neuberg-Str.1, D-30625 Hannover, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Greulich
authors.affiliation: Institut für Molekularbiologie, OE5250, Medizinische Hochschule Hannover, Carl-Neuberg-Str.1, D-30625 Hannover, Germany.
authors.forename: Mark-Oliver
authors.initials: MO
authors.lastname: Trowe
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, OE8050, Medizinische Hochschule Hannover, Carl-Neuberg-Str.1, D-30625 Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Leffler
authors.affiliation: Klinik für Anästhesiologie und Intensivmedizin, OE8050, Medizinische Hochschule Hannover, Carl-Neuberg-Str.1, D-30625 Hannover, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Stoetzer
authors.affiliation: Institut für Molekularbiologie, OE5250, Medizinische Hochschule Hannover, Carl-Neuberg-Str.1, D-30625 Hannover, Germany.
authors.forename: Henner F
authors.initials: HF
authors.lastname: Farin
authors.affiliation: Institut für Molekularbiologie, OE5250, Medizinische Hochschule Hannover, Carl-Neuberg-Str.1, D-30625 Hannover, Germany. Electronic address: kispert.andreas@mh-hannover.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
mesh_terms: D000818:Animals; D015415:Biomarkers; D016000:Cluster Analysis; D005260:Female; D005333:Fetus; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005804:Genes, Lethal; D006321:Heart / Q000196:embryology*; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012849:Sinoatrial Node / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics*; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D020825:T-Box Domain Proteins; C420983:Tbx18 protein, mouse
keywords: Conditional misexpression; Microarray; Pacemaker; Sinoatrial node; Tbx18; Tbx3; Working myocardium