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(Circulation Research. 2007;101:902.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Pitx2c and Nkx2-5 Are Required for the Formation and Identity of the Pulmonary Myocardium

Mathilda T.M. Mommersteeg, Nigel A. Brown, Owen W.J. Prall, Corrie de Gier-de Vries, Richard P. Harvey, Antoon F.M. Moorman, Vincent M. Christoffels

From the Heart Failure Research Center (M.T.M.M., C.d.G.-d.V., A.F.M.M., V.M.C.), Academic Medical Center, Amsterdam, The Netherlands; Division of Basic Medical Sciences (N.A.B.), St. George’s, University of London, England; Victor Chang Cardiac Research Institute (O.W.J.P., R.P.H.), Darlinghurst, Australia; and Faculties of Life Sciences and Medicine (R.P.H.), The University of New South Wales, Kensington, Australia.

Correspondence to Vincent M. Christoffels, Heart Failure Research Center, Academic Medical Centre, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands. E-mail v.m.christoffels{at}amc.uva.nl

The pulmonary vein is sleeved by myocardium, which is a major source of atrial fibrillation and is involved in congenital sinus venosus defects. Little is known about the cellular origin and mechanism of formation of the pulmonary myocardium. We observed a biphasic process of pulmonary myocardium formation in mice. Firstly, a myocardial cell population forms de novo at the connection of the pulmonary vein and the atrium. Genetic labeling revealed that atrial cells do not contribute to this population, indicating it forms by differentiation of pulmonary mesenchymal cells. Secondly, these pulmonary myocardial cells initiate a phase of rapid proliferation and form the pulmonary myocardial sleeve. Pitx2c-deficient mice do not develop a pulmonary myocardial sleeve because they fail to form the initial pulmonary myocardial cells. Genetic-labeling analyses demonstrated that whereas the systemic venous return derives from Nkx2-5–negative precursors, the pulmonary myocardium derives from Nkx2-5–expressing precursors, indicating a distinct origin of the 2 venous systems. Nkx2-5 and its target gap-junction gene Cx40 are expressed in the atria and in the pulmonary myocardium but not in the systemic venous return, which expresses the essential pacemaker channel Hcn4. When Nkx2-5 protein level was lowered in a hypomorphic model, the pulmonary myocardium switched to a Cx40-negative, Hcn4-positive phenotype resembling that of the systemic venous return. In conclusion, our data suggest a cellular mechanism for pulmonary myocardium formation and highlight the key roles played by Pitx2c and Nkx2-5 in its formation and identity.

Key Words: pulmonary myocardium • pulmonary vein • Nkx2-5 • Pitx2c • Hcn4 • Cx40 • differentiation • lineage • precursor

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