title: Nkx genes are essential for maintenance of ventricular identity.
abstract: Establishment of specific characteristics of each embryonic cardiac chamber is crucial for development of a fully functional adult heart. Despite the importance of defining and maintaining unique features in ventricular and atrial cardiomyocytes, the regulatory mechanisms guiding these processes are poorly understood. Here, we show that the homeodomain transcription factors Nkx2.5 and Nkx2.7 are necessary to sustain ventricular chamber attributes through repression of atrial chamber identity. Mutation of nkx2.5 in zebrafish yields embryos with diminutive ventricular and bulbous atrial chambers. These chamber deformities emerge gradually during development, with a severe collapse in the number of ventricular cardiomyocytes and an accumulation of excess atrial cardiomyocytes as the heart matures. Removal of nkx2.7 function from nkx2.5 mutants exacerbates the loss of ventricular cells and the gain of atrial cells. Moreover, in these Nkx-deficient embryos, expression of vmhc, a ventricular gene, fades, whereas expression of amhc, an atrial gene, expands. Cell-labeling experiments suggest that ventricular cardiomyocytes can transform into atrial cardiomyocytes in the absence of Nkx gene function. Through suggestion of transdifferentiation from ventricular to atrial fate, our data reveal a pivotal role for Nkx genes in maintaining ventricular identity and highlight remarkable plasticity in differentiated myocardium. Thus, our results are relevant to the etiologies of fetal and neonatal cardiac pathology and could direct future innovations in cardiac regenerative medicine.
authors.affiliation: Developmental Genetics Program and Department of Cell Biology, Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Kimara L
authors.initials: KL
authors.lastname: Targoff
authors.forename: Sophie
authors.initials: S
authors.lastname: Colombo
authors.forename: Vanessa
authors.initials: V
authors.lastname: George
authors.forename: Thomas
authors.initials: T
authors.lastname: Schell
authors.forename: Seok-Hyung
authors.initials: SH
authors.lastname: Kim
authors.forename: Lilianna
authors.initials: L
authors.lastname: Solnica-Krezel
authors.forename: Deborah
authors.initials: D
authors.lastname: Yelon
mesh_terms: D000818:Animals; D024743:Atrial Myosins / Q000096:biosynthesis; D002454:Cell Differentiation; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006325:Heart Atria / Q000196:embryology* / Q000378:metabolism; D006352:Heart Ventricles / Q000196:embryology* / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D024723:Ventricular Myosins / Q000096:biosynthesis; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C528182:Nkx2.5 protein, zebrafish; C102934:Nkx2.7 protein, zebrafish; D014157:Transcription Factors; D029961:Zebrafish Proteins; D024743:Atrial Myosins; D024723:Ventricular Myosins
keywords: Atrium; Chamber identity; Ventricle; Zebrafish; nkx2.5; nkx2.7
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