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The Forkhead Box C1 ( FOXC1 ) gene encodes a forkhead/winged helix transcription factor involved in embryonic development. Mutations in this gene cause dysgenesis of the anterior segment of the eye, most commonly Axenfeld-Rieger syndrome (ARS), often with other systemic features. The developmental mechanisms and pathways regulated by  FOXC1  remain largely unknown. There are two conserved orthologs of  FOXC1  in zebrafish,  foxc1a  and  foxc1b . To further examine the role of  FOXC1  in vertebrates, we generated  foxc1a  and  foxc1b  single knockout zebrafish lines and bred them to obtain various allelic combinations. Three genotypes demonstrated visible phenotypes:  foxc1a   −/−   single homozygous and  foxc1  −/−  double knockout homozygous embryos presented with similar characteristics comprised of severe global vascular defects and early lethality, as well as microphthalmia, periocular edema and absence of the anterior chamber of the eye; additionally, fish with heterozygous loss of  foxc1a  combined with homozygosity for  foxc1b  ( foxc1a  +/− ; foxc1b  −/− ) demonstrated craniofacial defects, heart anomalies and scoliosis. All other single and combined genotypes appeared normal. Analysis of  foxc1  expression detected a significant increase in  foxc1a  levels in homozygous and heterozygous mutant eyes, suggesting a mechanism for  foxc1a  upregulation when its function is compromised; interestingly, the expression of another ARS-associated gene,  pitx2 , was responsive to the estimated level of wild-type Foxc1a, indicating a possible role for this protein in the regulation of  pitx2  expression. Altogether, our results support a conserved role for  foxc1  in the formation of many organs, consistent with the features observed in human patients, and highlight the importance of correct  FOXC1/foxc1  dosage for vertebrate development.

Disruption of foxc1 genes in zebrafish results in dosage-dependent phenotypes overlapping Axenfeld-Rieger syndrome