Pleiotropy in FOXC1 -attributable phenotypes involves altered ciliation and cilia-dependent signaling

Alterations 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 the transcription factor . Here, we show that patients with -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 length . 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 two murine mutant strains demonstrated altered axonemal length in the choroid plexus with the increased expression of an essential regulator of multi-ciliation, . The novel complexity revealed in ciliation of the choroid plexus indicates a partitioning of function between these transcription factors. Collectively, these results support a contribution from ciliary dysfunction to some -induced phenotypes.