2007 Fiscal Year Final Research Report Summary
Clarification of vascular smooth muscle cell differentiation by Notch signaling
| Project/Area Number |
18590800
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Gunma University |
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Principal Investigator |
ISO Tatsuya Gunma University, Graduate School of Medicine, assistant professor (10400756)
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| Co-Investigator(Kenkyū-buntansha) |
KURABAYASHI Masahiko Gunma University, Graduate School of Medicine, professor (00215047)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Notch signaling / myocardin / smooth muscle cell differentiation / Jagged1 / Dll4 / RBP-Jk / SRF |
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| Research Abstract |
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 (NICD), an activated form of Notch, upregulates 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 γ-secretase inhibitor, DAPT, which impedes Notch signaling. Using RBP-Jκ-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-Jκ, 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-Jκ-dependent mechanism and augments gene expression mediated by 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 VSMC phenotype.
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Research Products
(22 results)
