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Development, Vol 125, Issue 22 4359-4367, Copyright © 1998 by Company of Biologists

JOURNAL ARTICLES

Neurofibromin modulation of ras activity is required for normal endocardial-mesenchymal transformation in the developing heart

MM Lakkis and JA Epstein
Cardiology Division, Department of Medicine and the Department of Cell and Molecular Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

Endocardial cushions are the precursors of the cardiac valves and form by a process of epithelial-mesenchymal transformation. Secreted growth factors from myocardium induce endocardial cells to transform into mesenchyme and invade the overlying extracellular matrix. Here, we show that the product of the Nf1 neurofibromatosis gene is required to regulate this event. In the absence of neurofibromin, mouse embryo hearts develop overabundant endocardial cushions due to hyperproliferation and lack of normal apoptosis. Neurofibromin deficiency in explant cultures is reproduced by activation of ras signaling pathways, and the Nf1(-/-) mutant phenotype is prevented by inhibiting ras in vitro. These results indicate that neurofibromin normally acts to modulate epithelial-mesenchymal transformation and proliferation in the developing heart by down regulating ras activity.
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