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A Role for microRNAs in Axenfeld Rieger Syndrome and Craniofacial/Tooth Anomalies
Author(s) -
Amendt Brad A.,
Cao Huojun,
Wang Jianbo,
Li Xiao,
Gutierrez Diana
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.334.2
Subject(s) - microrna , biology , noggin , pitx2 , conditional gene knockout , wnt signaling pathway , craniofacial , homeobox , microbiology and biotechnology , transcription factor , genetics , gene , signal transduction , bone morphogenetic protein , phenotype
Mutations in the PITX2 homeobox gene are associated with Axenfeld Rieger syndrome (ARS) and defective PITX2 transcriptional activity affects microRNA expression. Methods Conditional knockout and transgenic mice, molecular and biochemical assays reveal molecular mechanisms of specific microRNAs and a regulated network for their expression. Results We have identified discrete sets of mircoRNAs expressed at various stages of craniofacial development. Conditional knockout (cKO) of Dicer1 (mature microRNAs) in the dental and oral epithelium using the Pitx2 Cre mice results in multiple and branched enamel‐free incisors, cusp‐less molars and cleft palate. The cervical loop (stem cell niche) is expanded in Dicer1 cKO and epithelial cell differentiation is repressed. PITX2 regulates the expression of microRNAs that target Noggin, a potent BMP inhibitor, Lef‐1/Wnt‐β‐catenin signaling and HMGN2 a chromatin‐associated remodeling factor. PITX2 positively and negatively regulates a novel microRNA‐gene expression network involved in progenitor cell (stem cell) proliferation and differentiation. Conclusions PITX2 regulates microRNA expression and microRNAs feedback to regulate PITX2 expression through several novel molecular mechanisms. Support for this research was provided from grants DE13941 and DE18885 from the National Institute of Dental and Craniofacial Research.