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Abstract
ABSTRACTIrf6 and Esrp1 are important for palate development across vertebrates. In zebrafish, we found that irf6 regulates the expression of esrp1. We detailed overlapping Irf6 and Esrp1/2 expression in mouse orofacial epithelium. In zebrafish, irf6 and esrp1/2 share expression in periderm, frontonasal ectoderm and oral epithelium. Genetic disruption of irf6 and esrp1/2 in zebrafish resulted in cleft of the anterior neurocranium. The esrp1/2 mutant also developed cleft of the mouth opening. Lineage tracing of cranial neural crest cells revealed that the cleft resulted not from migration defect, but from impaired chondrogenesis. Analysis of aberrant cells within the cleft revealed expression of sox10, col1a1 and irf6, and these cells were adjacent to krt4+ and krt5+ cells. Breeding of mouse Irf6; Esrp1; Esrp2 compound mutants suggested genetic interaction, as the triple homozygote and the Irf6; Esrp1 double homozygote were not observed. Further, Irf6 heterozygosity reduced Esrp1/2 cleft severity. These studies highlight the complementary analysis of Irf6 and Esrp1/2 in mouse and zebrafish, and identify a unique aberrant cell population in zebrafish expressing sox10, col1a1 and irf6. Future work characterizing this cell population will yield additional insight into cleft pathogenesis.
Highlights
IntroductionDevelopment of vertebrate craniofacial structures requires coordinated cellular induction, migration, proliferation and differentiation, which allow for the positioning of adjacent epithelial-lined facial processes that merge (Reid et al, 2011; O’Donoghue et al, 2020; Knight and Schilling, 2006; Jiang et al, 2006; Helms et al, 2005; Dougherty et al, 2012; Creuzet et al, 2005; Cordero et al, 2011; Abramyan and Richman, 2015)
We found that Irf6, Esrp1 and Esrp2 were expressed with high levels of expression in areas of craniofacial development (Fig. 3A)
We found that Irf6R84C/+ heterozygotes exhibited a shorter palate than WT (Fig. 9A,B)
Summary
Development of vertebrate craniofacial structures requires coordinated cellular induction, migration, proliferation and differentiation, which allow for the positioning of adjacent epithelial-lined facial processes that merge (Reid et al, 2011; O’Donoghue et al, 2020; Knight and Schilling, 2006; Jiang et al, 2006; Helms et al, 2005; Dougherty et al, 2012; Creuzet et al, 2005; Cordero et al, 2011; Abramyan and Richman, 2015). Handling Editor: Patrick Tam Received 26 June 2020; Accepted 2 November 2020 palate requires convergence of the medial and lateral nasal prominences and the fusion of the secondary palatal shelves at the midline (Losa et al, 2018; Jiang et al, 2006; Abramyan and Richman, 2015). Failure of these processes to fuse results in orofacial clefts of the lip, primary palate or secondary palate (GritliLinde, 2008). IRF6 disruption is causal for syndromic cleft in Van der Woude and popliteal pterygium syndromes, and associated with non-syndromic orofacial clefts (Zucchero et al, 2004; Leslie et al, 2013; Kondo et al, 2002; Beaty et al, 2016)
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