title: Slow progressive conduction and contraction defects in loss of Nkx2-5 mice after cardiomyocyte terminal differentiation.
abstract: Mutations in homeoprotein NKX2-5 are linked to human congenital heart disease, resulting in various cardiac anomalies, as well as in postnatal progressive conduction defects and occasional left ventricular dysfunction; yet the function of Nkx2-5 in the postnatal period is largely unexplored. In the heart, the majority of cardiomyocytes are believed to complete cell-cycle withdrawal shortly after birth, which is generally accompanied by a re-organization of chromatin structure shown in other tissues. We reasoned that the effects of the loss of Nkx2-5 in mice may be different after cell-cycle withdrawal compared with those of the perinatal loss of Nkx2-5, which results in rapid conduction and contraction defects within 4 days after the deletion of Nkx2-5 alleles (Circ Res. 2008;103:580). In this study, floxed-Nkx2-5 alleles were deleted using tamoxifen-inducible Cre transgene (Cre-ER) beginning at 2 weeks of age. The loss of Nkx2-5 beginning at 2 weeks of age resulted in conduction and contraction defects similar to the perinatal loss of Nkx2-5, however, with a substantially slower disease progression shown by 1 degrees atrioventricular block at 6 weeks of age (4 weeks after tamoxifen injections) and heart enlargement after 12 weeks of age (10 weeks after tamoxifen injections). The phenotypes were accompanied by a slower and smaller degree of reduction of several critical Nkx2-5 downstream targets that were observed in mice with a perinatal loss of Nkx2-5. These results suggest that Nkx2-5 is necessary for proper conduction and contraction after 2 weeks of age, but with a substantially distinct level of necessity at 2 weeks of age compared with that in the perinatal period.
authors: Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610-0274, USA.
authors: Morihiko
authors: M
authors: Takeda
authors: Laura E
authors: LE
authors: Briggs
authors: Hiroko
authors: H
authors: Wakimoto
authors: Melissa H
authors: MH
authors: Marks
authors: Sonisha A
authors: SA
authors: Warren
authors: Jonathan T
authors: JT
authors: Lu
authors: Ellen O
authors: EO
authors: Weinberg
authors: Keith D
authors: KD
authors: Robertson
authors: Kenneth R
authors: KR
authors: Chien
authors: Hideko
authors: H
authors: Kasahara
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D002454:Cell Differentiation / Q000502:physiology; D015536:Down-Regulation; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System / Q000503:physiopathology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000473:pathology / Q000502:physiology; D013686:Telemetry; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors