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J. Biol. Chem., Vol. 281, Issue 39, 28555-28564, September 29, 2006
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Jagged1-selective Notch Signaling Induces Smooth Muscle Differentiation via a RBP-J
-dependent Pathway*
¶1
From the
Department of Medicine and Biological Science, Education and Research Center, ¶Laboratory Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8511 and the ||Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo 113-0033, Japan
The Notch signaling pathway plays a crucial role in specifying cellular fates by interaction between cellular neighbors; however, the molecular mechanism underlying smooth muscle cell (SMC) differentiation by Notch signaling has not been well characterized. Here we demonstrate that Jagged1-Notch signaling promotes SMC differentiation from mesenchymal cells. Overexpression of the Notch intracellular domain, an activated form of Notch, up-regulates the expression of multiple SMC marker genes including SMC-myosin heavy chain (Sm-mhc) in mesenchymal 10T1/2 cells, but not in non-mesenchymal cells. Physiological Notch stimulation by its ligand Jagged1, but not Dll4, directly induces Sm-mhc expression in 10T1/2 cells without de novo protein synthesis, indicative of a ligand-selective effect. Jagged1-induced expression of SM-MHC was blocked by
-secretase inhibitor, N-(N-(3,5-difluorophenyl)-L-alanyl)-S-phenylglycine t-butyl ester, which impedes Notch signaling. Using Rbp-j
-deficient cells and site-specific mutagenesis of the SM-MHC gene, we show that such an induction is independent of the myocardin-serum response factor-CArG complex, but absolutely dependent on RBP-J, a major mediator of Notch signaling, and its cognate binding sequence. Of importance, Notch signaling and myocardin synergistically activate SM-MHC gene expression. Taken together, these data suggest that the Jagged1-Notch pathway constitutes an instructive signal for SMC differentiation through an RBP-J-dependent mechanism and augments gene expression mediated by the myocardin-SRF-CArG complex. Given that Notch pathway components are expressed in vascular SMC during normal development and disease, Notch signaling is likely to play a pivotal role in such situations to modulate the vascular smooth muscle cell phenotype.
Received for publication, March 23, 2006 , and in revised form, July 24, 2006.
* This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture of Japan, a grant from the Japan Cardiovascular Foundation (to M. K.), and a Japan Heart Foundation Grant for Research on Atherosclerosis Update (to T. I.). 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.
1 To whom correspondence should be addressed: Gunma University Graduate School of Medicine 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan. Tel.: 81-27-220-8140; Fax: 81-27-220-8150; E-mail: mkuraba{at}med.gunma-u.ac.jp.
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