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J. Biol. Chem., Vol. 280, Issue 23, 22278-22286, June 10, 2005

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The Forkhead Box M1 Transcription Factor Is Essential for Embryonic Development of Pulmonary Vasculature^*

Il-Man Kim, Sneha Ramakrishna, Galina A. Gusarova, Helena M. Yoder, Robert H. Costa, and Vladimir V. Kalinichenko¶||

From the Department of Medicine and ^¶Committee on Developmental Biology, The University of Chicago, Chicago, Illinois 60637 and Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60607

Transgenic and gene knock-out studies demonstrated that the mouse Forkhead Box m1 (Foxm1 or Foxm1b) transcription factor (previously called HFH-11B, Trident, Win, or MPP2) is essential for hepatocyte entry into mitosis during liver development, regeneration, and liver cancer. Targeted deletion of Foxm1 gene in mice produces an embryonic lethal phenotype due to severe abnormalities in the development of liver and heart. In this study, we show for the first time that Foxm1^–/– lungs exhibit severe hypertrophy of arteriolar smooth muscle cells and defects in the formation of peripheral pulmonary capillaries as evidenced by significant reduction in platelet endothelial cell adhesion molecule 1 staining of the distal lung. Consistent with these findings, significant reduction in proliferation of the embryonic Foxm1^–/– lung mesenchyme was found, yet proliferation levels were normal in the Foxm1-deficient epithelial cells. Severe abnormalities of the lung vasculature in Foxm1^–/– embryos were associated with diminished expression of the transforming growth factor receptor II, a disintegrin and metalloprotease domain 17 (ADAM-17), vascular endothelial growth factor receptors, Polo-like kinase 1, Aurora B kinase, laminin 4 (Lama4), and the Forkhead Box f1 transcription factor. Cotransfection studies demonstrated that Foxm1 stimulates transcription of the Lama4 promoter, and this stimulation requires the Foxm1 binding sites located between –1174 and –1145 bp of the mouse Lama4 promoter. In summary, development of mouse lungs depends on the Foxm1 transcription factor, which regulates expression of genes essential for mesenchyme proliferation, extracellular matrix remodeling, and vasculogenesis.

Received for publication, January 25, 2005 , and in revised form, March 29, 2005.

^* This work was supported by The American Heart Association Scientist Development Grant 0335036N (to V. V. K.) and U. S. Public Health Service Grant DK 54687-06 (to R. H. C.) from NIDDK, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Medicine, The University of Chicago, 5841 S. Maryland Ave., MC 6076, Chicago, IL 60637. Tel.: 773-702-4024; Fax: 773-702-6500; E-mail: vkalin{at}medicine.bsd.uchicago.edu.

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