AP-2α and AP-2β cooperatively function in the craniofacial surface ectoderm to regulate chromatin and gene expression dynamics during facial development
- University of Iowa, United States
- University of Colorado Anschutz Medical Campus, United States
- University of Oklahoma Health Sciences Center, United States
Abstract
The facial surface ectoderm is essential for normal development of the underlying cranial neural crest cell populations, providing signals that direct appropriate growth, patterning, and morphogenesis. Despite the importance of the ectoderm as a signaling center, the molecular cues and genetic programs implemented within this tissue are understudied. Here we show that removal of two members of the AP-2 transcription factor family, AP-2α and AP-2ß, within the early embryonic ectoderm of the mouse leads to major alterations in the craniofacial complex. Significantly, there are clefts in both the upper face and mandible, accompanied by fusion of the upper and lower jaws in the hinge region. Comparison of ATAC-seq and RNA-seq analyses between controls and mutants revealed significant changes in chromatin accessibility and gene expression centered on multiple AP-2 binding motifs associated with enhancer elements within these ectodermal lineages. In particular, loss of these AP-2 proteins affects both skin differentiation as well as multiple signaling pathways, most notably the WNT pathway. We also determined that the mutant clefting phenotypes that correlated with reduced WNT signaling could be rescued by Wnt1 ligand overexpression in the ectoderm. Collectively, these findings highlight a conserved ancestral function for AP-2 transcription factors in ectodermal development and signaling, and provide a framework from which to understand the gene regulatory network operating within this tissue that directs vertebrate craniofacial development.
Data availability
Sequencing data has been deposited in the Gene Expression Omnibus under accession code GSE199342.
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ATAC-seq, histone-seq, and RNA-seq of mouse craniofacial tissuesNCBI Gene Expression Omnibus, GSE199342.
Article and author information
Author details
Funding
National Institute of Dental and Craniofacial Research (2R01 DE12728)
- Trevor Williams
National Institute of Dental and Craniofacial Research
- Eric Van Otterloo
University of Iowa
- Eric Van Otterloo
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Paul Trainor
Ethics
Animal experimentation: All experiments were conducted in accordance with all applicable guidelines and regulations, following the 'Guide for the Care and Use of Laboratory Animals of the National Institutes of Health'. The animal protocol utilized was approved by the Institutional Animal Care and Use Committee of the University of Colorado - Anschutz Medical Campus (#14) and the Institutional Animal Care and Use Committee of the University of Iowa (#9012197).
Version history
- Received: May 19, 2021
- Preprint posted: June 10, 2021 (view preprint)
- Accepted: March 22, 2022
- Accepted Manuscript published: March 25, 2022 (version 1)
- Version of Record published: April 25, 2022 (version 2)
Copyright
© 2022, Van Otterloo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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AP-2α and AP-2β cooperatively function in the craniofacial surface ectoderm to regulate chromatin and gene expression dynamics during facial development
eLife 11:e70511.
https://doi.org/10.7554/eLife.70511
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