Pleiotropy inFOXC1-attributable phenotypes involves altered ciliation and cilia-dependent signaling

AbstractAlterations to cilia are responsible for a wide range of severe disease; however, understanding of the transcriptional control of ciliogenesis remains incomplete. We evaluated whether ciliary dysfunction contributed to the pleiotropic phenotypes caused by theForkheadtranscription factorFOXC1. Here, we show that patients withFOXC1-attributable Axenfeld-Rieger Syndrome (ARS) have a prevalence of ciliopathy-associated phenotypes comparable to syndromic ciliopathies. We demonstrate that altering the level of Foxc1, via shRNA mediated inhibition and mRNA overexpression, modifies cilia lengthin vitro. These structural changes were associated with substantially perturbed cilia-dependent signaling [Hedgehog (Hh) and PDGFRα] and the altered ciliary compartmentalization of a major Hh pathway transcription factor, Gli2. Analyses of twoFoxc1murine mutant strains demonstrated altered axonemal length in the choroid plexus with the increased expression of an essential regulator of multi-ciliation,Foxj1. The novel complexity revealed in ciliation of the choroid plexus indicates a partitioning of function between theseForkheadtranscription factors. Collectively, these results support a contribution from ciliary dysfunction to someFOXC1-induced phenotypes.