Pitx2-Sox2-Lef1 interactions specify progenitor oral/dental epithelial cell signaling centers

Wenjie Yu; Zhao Sun; Yan Sweat; Mason Sweat; Shankar Rengasamy Venugopalan; Steven Eliason; Huojun Cao; Michael L Paine; Brad A Amendt

doi:10.1242/dev.186023

Pitx2-Sox2-Lef1 interactions specify progenitor oral/dental epithelial cell signaling centers

Development. 2020 Jun 4;147(11):dev186023. doi: 10.1242/dev.186023.

Authors

Wenjie Yu¹, Zhao Sun^{1

2}, Yan Sweat¹, Mason Sweat¹, Shankar Rengasamy Venugopalan³, Steven Eliason¹, Huojun Cao³, Michael L Paine⁴, Brad A Amendt^{5

3}

Affiliations

¹ Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA.
² Division of Nephrology, Washington University School of Medicine, St Louis, MO 63110, USA.
³ Iowa Institute for Oral Health Research, College of Dentistry, The University of Iowa, Iowa City, IA 52242, USA.
⁴ Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA.
⁵ Department of Anatomy and Cell Biology, and the Craniofacial Anomalies Research Center, The University of Iowa, Iowa City, IA 52242, USA [email protected].

Abstract

Epithelial signaling centers control epithelial invagination and organ development, but how these centers are specified remains unclear. We report that Pitx2 (the first transcriptional marker for tooth development) controls the embryonic formation and patterning of epithelial signaling centers during incisor development. We demonstrate using Krt14^Cre /Pitx2^flox/flox (Pitx2^cKO ) and Rosa26^CreERT/Pitx2^flox/flox mice that loss of Pitx2 delays epithelial invagination, and decreases progenitor cell proliferation and dental epithelium cell differentiation. Developmentally, Pitx2 regulates formation of the Sox2⁺ labial cervical loop (LaCL) stem cell niche in concert with two signaling centers: the initiation knot and enamel knot. The loss of Pitx2 disrupted the patterning of these two signaling centers, resulting in tooth arrest at E14.5. Mechanistically, Pitx2 transcriptional activity and DNA binding is inhibited by Sox2, and this interaction controls gene expression in specific Sox2 and Pitx2 co-expression progenitor cell domains. We demonstrate new transcriptional mechanisms regulating signaling centers by Pitx2, Sox2, Lef1 and Irx1.

Keywords: Craniofacial/tooth development; Dental epithelial stem cells; Enamel knot; Irx1; Pitx2; Shh; Signaling centers; Sox2; Stem cell niche; Transcriptional regulation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Differentiation
Cell Proliferation
Dental Enamel / metabolism
Embryo, Mammalian / metabolism
Epithelial Cells / cytology
Epithelial Cells / metabolism*
Gene Expression Regulation, Developmental
Hedgehog Proteins / metabolism
Homeobox Protein PITX2
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism*
Lymphoid Enhancer-Binding Factor 1 / genetics
Lymphoid Enhancer-Binding Factor 1 / metabolism*
Mice
Mice, Knockout
Odontogenesis
SOXB1 Transcription Factors / genetics
SOXB1 Transcription Factors / metabolism*
Signal Transduction*
Stem Cell Niche
Stem Cells / cytology
Stem Cells / metabolism
Tooth / cytology
Tooth / growth & development
Tooth / metabolism
Transcription Factors / deficiency
Transcription Factors / genetics
Transcription Factors / metabolism*
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
Hedgehog Proteins
Homeodomain Proteins
Irx1 protein, mouse
Lef1 protein, mouse
Lymphoid Enhancer-Binding Factor 1
SOXB1 Transcription Factors
Shh protein, mouse
Sox2 protein, mouse
Transcription Factors
YAP-Signaling Proteins
Yap1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding