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Published online April 14, 2008
doi:10.1083/jcb.200708197
The Journal of Cell Biology, Vol. 181, No. 2, 367-380
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Nath et al.
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Article

 Leptin affects endocardial cushion formation by modulating EMT and migration via Akt signaling cascades

Anjali K. Nath1,2, Rachel M. Brown1, Michael Michaud1, M. Rocio Sierra-Honigmann3, Michael Snyder2, and Joseph A. Madri1

1 Department of Pathology, School of Medicine, and 2 Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06510
3 Department of Plastic Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048

Correspondence to Joseph A. Madri: joesph.madri{at}yale.edu

Blood circulation is dependent on heart valves to direct blood flow through the heart and great vessels. Valve development relies on epithelial to mesenchymal transition (EMT), a central feature of embryonic development and metastatic cancer. Abnormal EMT and remodeling contribute to the etiology of several congenital heart defects. Leptin and its receptor were detected in the mouse embryonic heart. Using an ex vivo model of cardiac EMT, the inhibition of leptin results in a signal transducer and activator of transcription 3 and Snail/vascular endothelial cadherin–independent decrease in EMT and migration. Our data suggest that an Akt signaling pathway underlies the observed phenotype. Furthermore, loss of leptin phenocopied the functional inhibition of {alpha}vβ3 integrin receptor and resulted in decreased {alpha}vβ3 integrin and matrix metalloprotease 2, suggesting that the leptin signaling pathway is involved in adhesion and migration processes. This study adds leptin to the repertoire of factors that mediate EMT and, for the first time, demonstrates a role for the interleukin 6 family in embryonic EMT.

Abbreviations used in this paper: AVC, atrioventricular canal; EMT, epithelial to mesenchymal transition; F-actin, filamentous actin; Il-6, interleukin 6; JAK, Janus kinase; MMP, matrix metalloprotease; OSM, oncostatin M; PCNA, proliferating cell nuclear antigen; PI3K, phosphoinositide-3 kinase; STAT, signal transducer and activator of transcription; VE, vascular endothelial.


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