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Published online May 5, 2008
doi:10.1083/jcb.200711145
The Journal of Cell Biology, Vol. 181, No. 3, 461-473
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Shang et al.
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Article

 Pitx2 is functionally important in the early stages of vascular smooth muscle cell differentiation

Yueting Shang1, Tadashi Yoshida1, Brad A. Amendt2, James F. Martin2, and Gary K. Owens1

1 Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908
2 Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030

Correspondence to Gary K. Owens: gko{at}virginia.edu

Mechanisms that control vascular smooth muscle cell (SMC) differentiation are poorly understood. We identify Pitx2 as a previously unknown homeodomain transcription factor that is rapidly induced in an in vitro model of SMC differentiation from multipotent stem cells. Pitx2 induces expression of multiple SMC differentiation marker genes by binding to a TAATC(C/T) cis-element, by interacting with serum response factor, and by increasing histone acetylation levels within the promoters of SMC differentiation marker genes. Suppression of Pitx2 reduces expression of SMC differentiation marker genes in the early stages of SMC differentiation in vitro, whereas Prx1, another homeodomain protein, regulates SMC differentiation marker genes in fully differentiated SMCs. Pitx2, but not Prx1, knockout mouse embryos exhibit impaired induction of SMC differentiation markers in the dorsal aorta and branchial arch arteries. Our results demonstrate that Pitx2 functions to regulate the early stages of SMC differentiation.

Y. Shang and T. Yoshida contributed equally to this work.

Abbreviations used in this paper: ACLP, aortic carboxypeptidase-like protein; ChIP, chromatin immunoprecipitation; E, embryonic day; EMSA, electrophoresis mobility shift assay; ES, embryonic stem; HDAC, histone deacetylase; RA, all transretinoic acid; SM, smooth muscle; SMC, SM cell; SRF, serum response factor; SSEA-1, stage-specific embryonic antigen–1.


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