The Axenfeld–Rieger Syndrome Gene FOXC1 Contributes to Left–Right Patterning

Precise spatiotemporal expression of the Nodal-Lefty-Pitx2 cascade in lateral plate mesoderm establishes left–right axis, which provides vital cues for correct organ formation and function. Mutations one constituent PITX2 and, separately, Forkhead transcription factor FOXC1 independently cause a multi-system disorder known as Axenfeld–Rieger syndrome (ARS). Since cardiac involvement is an established ARS phenotype because disrupted patterning can congenital heart defects, we investigated zebrafish whether foxc1 contributes to laterality or situs. We demonstrate that CRISPR/Cas9-generated foxc1a foxc1b mutants exhibit abnormal looping prevalence situs defects increased foxc1a−/−; foxc1b−/− homozygotes. Similarly, double homozygotes isomerism liver pancreas, are key features gut Placement asymmetric visceral organs relative midline was also perturbed by mRNA overexpression foxc1b. In addition, analysis components, identified mutants, reduced abolished NODAL antagonist lefty2. Together, these data reveal novel contribution from patterning, demonstrating this role sensitive gene dosage, provide plausible mechanism incidence patients.