Perinatal loss of Nkx2-5 results in rapid conduction and contraction defects.
Homeobox transcription factor Nkx2-5, highly expressed in heart, is a critical factor during early embryonic cardiac development. In this study, using tamoxifen-inducible Nkx2-5 knockout mice, we demonstrate the role of Nkx2-5 in conduction and contraction in neonates within 4 days after perinatal tamoxifen injection. Conduction defect was accompanied by reduction in ventricular expression of the cardiac voltage-gated Na+ channel pore-forming alpha-subunit (Na(v)1.5-alpha), the largest ion channel in the heart responsive for rapid depolarization of the action potential, which leads to increased intracellular Ca2+ for contraction (conduction-contraction coupling). In addition, expression of ryanodine receptor 2, through which Ca2+ is released from sarcoplasmic reticulum, was substantially reduced in Nkx2-5 knockout mice. These results indicate that Nkx2-5 function is critical not only during cardiac development but also in perinatal hearts, by regulating expression of several important gene products involved in conduction and contraction.
Briggs
Laura E
LE
University of Florida College of Medicine, 1600 SW Archer Rd, M-540, Gainesville, FL 32610-0274, USA.
Takeda
Morihiko
M
Cuadra
Adolfo E
AE
Wakimoto
Hiroko
H
Marks
Melissa H
MH
Walker
Alexandra J
AJ
Seki
Tsugio
T
Oh
Suk P
SP
Lu
Jonathan T
JT
Sumners
Colin
C
Raizada
Mohan K
MK
Horikoshi
Nobuo
N
Weinberg
Ellen O
EO
Yasui
Kenji
K
Ikeda
Yasuhiro
Y
Chien
Kenneth R
KR
Kasahara
Hideko
H
D000200:Action Potentials / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism; D002645:Chickens; D006329:Heart Conduction System / Q000254:growth & development* / Q000502:physiology; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics*; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors