Nkx2.5 cell-autonomous gene function is required for the postnatal formation of the peripheral ventricular conduction system.
The ventricular conduction system is responsible for rapid propagation of electrical activity to coordinate ventricular contraction. To investigate the role of the transcription factor Nkx2.5 in the morphogenesis of the ventricular conduction system, we crossed Nkx2.5(+/-) mice with Cx40(eGFP/+) mice in which eGFP expression permits visualization of the His-Purkinje conduction system. Major anatomical and functional disturbances were detected in the His-Purkinje system of adult Nkx2.5(+/-)/Cx40(eGFP/+) mice, including hypoplasia of eGFP-positive Purkinje fibers and the disorganization of the Purkinje fiber network in the ventricular apex. Although the action potential properties of the individual eGFP-positive cells were normal, the deficiency of Purkinje fibers in Nkx2.5 haploinsufficient mice was associated with abnormalities of ventricular electrical activation, including slowed and decremented conduction along the left bundle branch. During embryonic development, eGFP expression in the ventricular trabeculae of Nkx2.5(+/-) hearts was qualitatively normal, with a measurable deficiency in eGFP-positive cells being observed only after birth. Chimeric analyses showed that maximal Nkx2.5 levels are required cell-autonomously. Reduced Nkx2.5 levels are associated with a delay in cell cycle withdrawal in surrounding GFP-negative myocytes. Our results suggest that the formation of the peripheral conduction system is time- and dose-dependent on the transcription factor Nkx2.5 that is cell-autonomously required for the postnatal differentiation of Purkinje fibers.
Meysen
Sonia
S
Institut de Biologie du Développement de Marseille-Luminy, IBDML, Université de la Méditerranée, CNRS UMR6216, Campus de Luminy, Marseille, France.
Marger
Laurine
L
Hewett
Kenneth W
KW
Jarry-Guichard
Thérèse
T
Agarkova
Irina
I
Chauvin
Jean Paul
JP
Perriard
Jean Claude
JC
Izumo
Seigo
S
Gourdie
Robert G
RG
Mangoni
Matteo E
ME
Nargeot
Joël
J
Gros
Daniel
D
Miquerol
Lucile
L
D000818:Animals; D002036:Bundle of His / Q000002:abnormalities / Q000254:growth & development / Q000502:physiology; D002454:Cell Differentiation; D004594:Electrophysiology; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006329:Heart Conduction System / Q000002:abnormalities / Q000254:growth & development* / Q000502:physiology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008955:Models, Cardiovascular; D011690:Purkinje Fibers / Q000002:abnormalities / Q000254:growth & development / Q000502:physiology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D016276:Ventricular Function
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D011994:Recombinant Proteins; D014157:Transcription Factors; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins