First Author | Takeda M | Year | 2009 |
Journal | Lab Invest | Volume | 89 |
Issue | 9 | Pages | 983-93 |
PubMed ID | 19546853 | Mgi Jnum | J:151895 |
Mgi Id | MGI:4355491 | Doi | 10.1038/labinvest.2009.59 |
Citation | Takeda M, et al. (2009) Slow progressive conduction and contraction defects in loss of Nkx2-5 mice after cardiomyocyte terminal differentiation. Lab Invest 89(9):983-93 |
abstractText | 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. |