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

ABSTRACT: 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.

SUBMITTER: Shang Y

PROVIDER: S-EPMC2364692 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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

Shang Yueting Y Yoshida Tadashi T Amendt Brad A BA Martin James F JF Owens Gary K GK

The Journal of cell biology 20080501 3

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 diffe ...[more]

PMID: 18458156

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Project description:Smad4 is a central mediator of transforming growth factor-?/bone morphogenetic protein signaling that controls numerous developmental processes as well as homeostasis in the adult. The present studies sought to understand the function of Smad4 expressed in vascular smooth muscle cells (VSMC) in vascular development and the underlying mechanisms.Breeding of Smad4(flox/flox) mice with SM22?-Cre mice resulted in no viable offspring with SM22?-Cre;Smad4(flox/flox) genotype in a total of 165 newborns. Subsequent characterization of 301 embryos between embryonic day (E) 9.5 and E14.5 demonstrated that mice with SM22?-Cre;Smad4(flox/flox) genotype died between E12.5 and E14.5 because of decreased cell proliferation and increased apoptosis in the embryonic heart and arteries. Additionally, deletion of Smad4 more specifically in SMC with the inducible smooth muscle myosin heavy chain (SMMHC)-Cre mice, in which decreased cell proliferation was observed only in the artery but not the heart, also caused lethality of the knockout embryos at E12.5 and E14.5. The Smad4-deficient VSMC lacked smooth muscle ?-actin filaments, decreased expression of SMC-specific gene markers, and markedly reduced cell proliferation, migration, and attachment. Using specific pharmacological inhibitors and small interfering RNAs, we demonstrated that inhibition of transforming growth factor-? signaling and its regulatory Smad 2/3 decreased VSMC proliferation, migration, and expression of SMC-specific gene markers, whereas inhibition of bone morphogenetic protein signaling only affected VSMC migration.SMC-specific deletion of Smad4 results in vascular defects that lead to embryonic lethality in mice, which may be attributed to decreased VSMC differentiation, proliferation, migration, as well as cell attachment and spreading. The transforming growth factor-? signaling pathway contributes to VSMC differentiation and function, whereas the bone morphogenetic protein signaling pathway regulates VSMC migration. These studies provide important insight into the role of Smad4 and its upstream Smads in regulating SMC function and vascular development of mice.

Dataset Information

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

Publications

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

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