A zebrafish model of foxe3 deficiency demonstrates lens and eye defects with dysregulation of key genes involved in cataract formation in humans

摘要: The Forkhead box E3 (FOXE3) gene encodes a transcription factor with forkhead/winged helix domain that is critical for development of the lens and anterior segment eye. Monoallelic biallelic deleterious sequence variants in FOXE3 cause aphakia, cataracts, sclerocornea microphthalmia humans. We used clustered regularly interspaced short palindromic repeats/Cas9 injections to target foxe3 transcript zebrafish order create an experimental model loss function this gene. Larvae were homozygous indel variant, c.296_300delTGCAG, predicting p.(Val99Alafs*2), demonstrated severe eye defects, including small or absent lenses microphthalmia. mutants showed more intense staining zl-1 antibody compared control lenses, consistent increased fiber cell differentiation. Whole genome transcriptome analysis (RNA-Seq) on RNA isolated from wildtype larvae defects putative homozygotes variant found significant dysregulation genes expressed whose orthologues are associated cataracts human patients, cryba2a, cryba1l1, mipa hsf4. Comparative RNA-seq data iSyTE identified several lens-enriched be down-regulated mutants. also noted upregulation lgsn crygmxl2 downregulation fmodb cx43.4, lens, but not yet phenotype These findings demonstrate new mutant highly relevant study regulatory networks conserved vertebrate development.