AP‐2α and AP‐2β Cooperatively Regulate Gene Expression of Ectodermal WNT Ligands to Drive Craniofacial Patterning

Abstract

Tissue‐tissue interactions are central to proper embryogenesis and are often disrupted in developmental disorders—providing an impetus to further understand their regulation. These interactions require coordinated molecular crosstalk (i.e., signaling molecules) between tissues, thus, providing the instructional cues necessary to generate complex anatomical structures. A prototypical example includes epithelial:mesenchymal interactions—necessary to pattern the craniofacial complex as well as central to the development of a variety of ectodermal appendages. While a great deal of information exists on both the molecules involved in crosstalk and their immediate transcriptional response in adjacent tissues, much less is known regarding how such signals are established. Here, through the use of conditional loss‐of‐function models of AP‐2 transcription factors (AP‐2α and AP‐2β) in mice, we reveal an essential, cooperative role for AP‐2α/β in driving expression of the genes encoding a variety of WNT ligands. Focusing on craniofacial development, loss of AP‐2α/β from the ectoderm results in major dysregulation of the WNT‐signaling pathway, dysregulation of downstream WNT target genes in adjacent tissues, and finally a profound impact on facial form. Importantly, genetic reduction of a WNT‐pathway inhibitor in AP‐2α/β ectoderm mutants can partially mitigate some of these defects. In addition, highlighting a broader role for AP‐2 in regulating WNT signaling, we find numerous WNT‐dependent ectodermal appendages are disrupted in AP‐2α/β ectoderm mutants. Ongoing work is being conducted to identify the molecular nature by which AP‐2 regulates Wnt ligand expression in the face as well as additional structures. Given WNT‐signaling components are often mutated in a variety of human craniofacial disorders and are key components of vertebrate facial evolution, these findings suggest that ectodermal AP‐2 regulation of WNT‐signaling is likely a key axis in these processes.Support or Funding InformationEVO NIH NIDCR K99 DE026823TW NIH NIDCR 2R01 DE012728 and 1R01 DE019843This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.