TY - JOUR T1 - Requirement of <em>Irf6</em> and <em>Esrp1/2</em> in frontonasal and palatal epithelium to regulate craniofacial and palate morphogenesis in mouse and zebrafish JF - bioRxiv DO - 10.1101/2020.06.14.149773 SP - 2020.06.14.149773 AU - Shannon H. Carroll AU - Claudio Macias Trevino AU - Edward B-H Li AU - Kenta Kawasaki AU - Nora Alhazmi AU - Shawn Hallett AU - Justin Cotney AU - Russ P. Carstens AU - Eric C. Liao Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/06/14/2020.06.14.149773.abstract N2 - 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 mouse and zebrafish embryonic oral epithelium and periderm. Genetic disruption of irf6 and esrp1/2 in the zebrafish resulted in cleft of the anterior neurocranium (ANC). In the esrp1/2 zebrafish mutant, cleft of the lip 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 interrupting ANC fusion revealed that this cell population espresses sox10 and irf6 and is adjacent to cells expressing epithelial krt4 and mesenchymal col1a1 genes. 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+, irf6+ cell population will yield additional insight into cleft pathogenesis.Competing Interest StatementThe authors have declared no competing interest. ER -