Dact2 represses PITX2 transcriptional activation and cell proliferation through Wnt/beta-catenin signaling during odontogenesis

Xiao Li; Sergio Florez; Jianbo Wang; Huojun Cao; Brad A Amendt

doi:10.1371/journal.pone.0054868

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Dact2 represses PITX2 transcriptional activation and cell proliferation through Wnt/beta-catenin signaling during odontogenesis

Journal article

Open access

Peer reviewed

Dact2 represses PITX2 transcriptional activation and cell proliferation through Wnt/beta-catenin signaling during odontogenesis

Xiao Li, Sergio Florez, Jianbo Wang, Huojun Cao and Brad A Amendt

PloS one, Vol.8(1), pp.e54868-e54868

2013

DOI: 10.1371/journal.pone.0054868

PMCID: PMC3551926

PMID: 23349981

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Abstract

Dact proteins belong to the Dapper/Frodo protein family and function as cytoplasmic attenuators in Wnt and TGFβ signaling. Previous studies show that Dact1 is a potent Wnt signaling inhibitor by promoting degradation of β-catenin. We report a new mechanism for Dact2 function as an inhibitor of the canonical Wnt signaling pathway by interacting with PITX2. PITX2 is a downstream transcription factor in Wnt/β-catenin signaling, and PITX2 synergizes with Lef-1 to activate downstream genes. Immunohistochemistry verified the expression of Dact2 in the tooth epithelium, which correlated with Pitx2 epithelial expression. Dact2 loss of function and PITX2 gain of function studies reveal a feedback mechanism for controlling Dact2 expression. Pitx2 endogenously activates Dact2 expression and Dact2 feeds back to repress Pitx2 transcriptional activity. A Topflash reporter system was employed showing PITX2 activation of Wnt signaling, which is attenuated by Dact2. Transient transfections demonstrate the inhibitory effect of Dact2 on critical dental epithelial differentiation factors during tooth development. Dact2 significantly inhibits PITX2 activation of the Dlx2 and amelogenin promoters. Multiple lines of evidence conclude the inhibition is achieved by the physical interaction between Dact2 and Pitx2 proteins. The loss of function of Dact2 also reveals increased cell proliferation due to up-regulated Wnt downstream genes, cyclinD1 and cyclinD2. In summary, we have identified a novel role for Dact2 as an inhibitor of the canonical Wnt pathway in embryonic tooth development through its regulation of cell proliferation and differentiation.

Signal Transduction

Transcriptional Activation - genetics

Cell Proliferation

Homeodomain Proteins - metabolism

Humans

Odontogenesis - genetics

Tooth - growth & development

Transcription Factors - genetics

Homeodomain Proteins - genetics

Transcription Factors - metabolism

Cell Differentiation - genetics

Animals

Wnt Signaling Pathway - genetics

Gene Expression Regulation, Developmental

Proteolysis

beta Catenin - antagonists & inhibitors

Adaptor Proteins, Signal Transducing - genetics

HEK293 Cells

Amelogenin - metabolism

Mice

Tooth - metabolism

Adaptor Proteins, Signal Transducing - metabolism

Details

Title: Subtitle: Dact2 represses PITX2 transcriptional activation and cell proliferation through Wnt/beta-catenin signaling during odontogenesis
Creators: Xiao Li - Department of Anatomy and Cell Biology, The University of Iowa, Iowa City, Iowa, USA
Sergio Florez
Jianbo Wang
Huojun Cao
Brad A Amendt
Resource Type: Journal article
Publication Details: PloS one, Vol.8(1), pp.e54868-e54868
DOI: 10.1371/journal.pone.0054868
PMID: 23349981
PMCID: PMC3551926
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: R01 DE013941 / NIDCR NIH HHS DE18885 / NIDCR NIH HHS R01 DE018885 / NIDCR NIH HHS DE13941 / NIDCR NIH HHS
Language: English
Date published: 2013
Academic Unit: Orthodontics; Anatomy and Cell Biology; Endodontics; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984025364502771

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