Cleft lip with or without cleft palate (CL/P) is the most common congenital craniofacial defect, with a frequency of 1 in 500 to 1 in 2500 live births depending on the population, and lifelong care can cost more than $100,000. In mice, secondary palate development occurs from E11.5 to E17.5, and consists of outgrowth, elevation, extension and fusion processes. At any stage during palatogenesis, the disruption of these processes could cause cleft palate, and these processes are all regulated in part by palatal mesenchyme.ObjectiveTo examine Six2, a transcription factor previously shown to play a role in craniofacial and kidney development, for a role in clefting predicted by the SYSFACE tool.MethodsSix2 knockout mice were generated and examined for clefting at different embryonic stages and P0 and craniofacial developmental defects.ResultsWe demonstrate that ablation of Six2 contributes to palatogenesis. We have characterized the clefting phenotype in Six2−/− embryos, demonstrating that the palate shelves fail to extend to the midline and contain premature ossified tissue compared to wild‐type (WT) littermates. The expression of Runx2 and its target Osx were higher in Six2−/− palates and surrounding maxilla with cleft than in control littermates. Histochemistry and immunohistochemistry experiments demonstrate premature ossification by specific cells in the Six2−/− palate.ConclusionsSix2 is a regulator of palate development and it acts by negatively regulating the ossification of palatal mesenchyme. In Six2−/− mice, ectopic ossification prevents the extension of the palate shelves causing cleft.Support or Funding InformationThe University of Iowa, College of DentistryThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Central corneal thickness is a quantitative trait with important associations to human health. In a phenotype-driven approach studying corneal thickness of congenic derivatives of C57BLKS/J and SJL/J mice, the critical region for a quantitative trait locus influencing corneal thickness, Cctq1a, was delimited to a 10-gene interval. Exome sequencing, RNAseq, and studying independent mutations eliminated multiple candidate genes and confirmed one. Though the causative gene, Tyr, has no obvious direct function in the transparent cornea, studies with multiple alleles on matched genetic backgrounds, both in isolation and genetic complementation crosses, confirmed allelism of Tyr-Cctq1a; albino mice lacking Tyr function had thin corneas. Albino mice also had increased axial length. Because albinism exposes eyes to increased light, the effect of dark-rearing was tested and found to rescue central corneal thickness. In sum, the results point to an epiphenomenon; developmental light exposure interacts with genotype as an important determinate of adult corneal thickness.
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