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Requirement of Irf6 and Esrp1/2 in frontonasal and palatal epithelium to regulate craniofacial and palate morphogenesis in mouse and zebrafish

Shannon H. Carroll, Claudio Macias Trevino, Edward B-H Li, Kenta Kawasaki, Nora Alhazmi, Shawn Hallett, Justin Cotney, Russ P. Carstens, Eric C. Liao
doi: https://doi.org/10.1101/2020.06.14.149773
Shannon H. Carroll
1Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
2Shriners Hospital for Children, Boston, MA 02114, USA
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Claudio Macias Trevino
1Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
3Harvard Medical School, Boston, MA 02115, USA
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Edward B-H Li
3Harvard Medical School, Boston, MA 02115, USA
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Kenta Kawasaki
1Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
2Shriners Hospital for Children, Boston, MA 02114, USA
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Nora Alhazmi
4Harvard School of Dental Medicine, Boston, MA 02115, USA
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Shawn Hallett
1Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
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Justin Cotney
7Department of Genetics and Genome Sciences, University of Connecticut Health, CT 06030, USA
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Russ P. Carstens
6Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Eric C. Liao
1Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
2Shriners Hospital for Children, Boston, MA 02114, USA
3Harvard Medical School, Boston, MA 02115, USA
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  • For correspondence: cliao@partners.org
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ABSTRACT

Orofacial clefts are among the most common human congenital malformations. Irf6 and Esrp1 are two key genes important for palate development, conserved across vertebrates. In the zebrafish, we found that irf6 regulates the expression of esrp1. Using RNAscope, we detailed overlapping Irf6 and Esrp1/2 gene expression in the mouse frontonasal prominence ectoderm, lambda joint periderm, palate and lip epithelium. In the zebrafish, irf6 and esrp1/2 share expression in the pre-gastrulation periderm and the embryonic frontonasal ectoderm, oral epithelium ventral to the anterior neurocranium (ANC), and the developing stomodeum. Genetic disruption of irf6 and esrp1/2 in the zebrafish resulted in cleft of the ANC. In the esrp1/2 zebrafish mutant, cleft of the mouth opening formed and appeared to tether into the ANC cleft. Lineage tracing of the anterior cranial neural crest cells revealed that cleft of the ANC resulted not from migration defect, but from impaired chondrogenesis. Molecular analysis of the aberrant cells localized within the ANC cleft revealed that this cell population espresses sox10, col1a1 and irf6 and is adjacent to cells expressing epithelial krt4. Detailed morphogenetic analysis of mouse Irf6 mutant revealed mesenchymal defects not observed in the Esrp1/2 mutant. Analysis of breeding compound Irf6;Esrp1;Esrp2 mutant suggests that these genes interact where the triple mutant is not observed. Taken together, these studies highlight the complementary analysis of Irf6 and Esrp1/2 in mouse and zebrafish models and captured an unique aberrant embryonic cell population that contributes to cleft pathogenesis. Future work characterizing this unqiue sox10+, col1a1+, irf6+ cell population will yield additional insight into cleft pathogenesis.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • SUMMARY STATEMENT These studies elucidate Irf6 and Esrp1/2 function in periderm and embryonic epithelium during palate development, using complementary mouse and zebrafish models. Mouse and zebrafish Irf6 and Esrp1/2 develop cleft lip and palate, where an aberrant mesenchymal/epithelial cell population is localized to the cleft in the esrp1/2 zebrafish mutant.

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Posted June 30, 2020.
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Requirement of Irf6 and Esrp1/2 in frontonasal and palatal epithelium to regulate craniofacial and palate morphogenesis in mouse and zebrafish
Shannon H. Carroll, Claudio Macias Trevino, Edward B-H Li, Kenta Kawasaki, Nora Alhazmi, Shawn Hallett, Justin Cotney, Russ P. Carstens, Eric C. Liao
bioRxiv 2020.06.14.149773; doi: https://doi.org/10.1101/2020.06.14.149773
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Requirement of Irf6 and Esrp1/2 in frontonasal and palatal epithelium to regulate craniofacial and palate morphogenesis in mouse and zebrafish
Shannon H. Carroll, Claudio Macias Trevino, Edward B-H Li, Kenta Kawasaki, Nora Alhazmi, Shawn Hallett, Justin Cotney, Russ P. Carstens, Eric C. Liao
bioRxiv 2020.06.14.149773; doi: https://doi.org/10.1101/2020.06.14.149773

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