Faculty Collaboration Database

Disruption of foxc1 genes in zebrafish results in dosage-dependent phenotypes overlapping Axenfeld-Rieger syndrome. Hum Mol Genet 2020 Sep 29;29(16):2723-2735

Date

07/29/2020

Pubmed ID

32720677

Pubmed Central ID

PMC7530528

DOI

10.1093/hmg/ddaa163

Scopus ID

2-s2.0-85092681312 (requires institutional sign-in at Scopus site)   14 Citations

Abstract

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.

Author List

Ferre-Fernández JJ, Sorokina EA, Thompson S, Collery RF, Nordquist E, Lincoln J, Semina EV

Authors

Ross F. Collery PhD Assistant Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
Joy Lincoln PhD Professor in the Pediatrics department at Medical College of Wisconsin
Elena V. Semina PhD Chief, Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
Elena A. Sorokina Research Scientist I in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Alleles
Animals
Anterior Eye Segment
Embryonic Development
Eye Abnormalities
Eye Diseases, Hereditary
Forkhead Transcription Factors
Gene Dosage
Gene Expression Regulation, Developmental
Genotype
Heart Defects, Congenital
Heterozygote
Homozygote
Humans
Mutation
Scoliosis
Transcription Factors
Zebrafish
Zebrafish Proteins