Slow progressive conduction and contraction defects in loss of Nkx2-5 mice after cardiomyocyte terminal differentiation

Morihiko Takeda, Laura E. Briggs, Hiroko Wakimoto, Melissa H. Marks, Sonisha A. Warren, Jonathan T. Lu, Ellen O. Weinberg, Keith D. Robertson, Kenneth R. Chien, Hideko Kasahara

Research output: Contribution to journalArticle

36 Scopus citations

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° 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.

Original languageEnglish (US)
Pages (from-to)983-993
Number of pages11
JournalLaboratory Investigation
Volume89
Issue number9
DOIs
StatePublished - Sep 1 2009

Keywords

  • Cardiomyocyte
  • Conduction defects
  • Gene targeting
  • Hypertrophy
  • Nkx2-5

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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    Takeda, M., Briggs, L. E., Wakimoto, H., Marks, M. H., Warren, S. A., Lu, J. T., Weinberg, E. O., Robertson, K. D., Chien, K. R., & Kasahara, H. (2009). Slow progressive conduction and contraction defects in loss of Nkx2-5 mice after cardiomyocyte terminal differentiation. Laboratory Investigation, 89(9), 983-993. https://doi.org/10.1038/labinvest.2009.59