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

Area of Science:

• Molecular Biology
• Developmental Biology
• Genetics

Background:

• Cilia are crucial cellular structures involved in various signaling pathways.
• Dysfunctional cilia lead to a spectrum of severe human diseases, known as ciliopathies.
• The transcriptional regulation of ciliogenesis and its role in FOXC1-related disorders are not fully understood.

Purpose of the Study:

• To investigate the role of cilia-mediated signaling in the diverse phenotypes associated with FOXC1.
• To determine if FOXC1 directly influences cilia structure and function.

Main Methods:

• Analysis of ciliopathy-associated phenotypes in patients with FOXC1-related Axenfeld-Rieger Syndrome (ARS).
• In vitro manipulation of Foxc1 protein levels (shRNA, CRISPR/Cas9, overexpression) to assess effects on cilia length.
• Assessment of cilia-dependent signaling pathways (Hedgehog, PDGFRα) and Gli2 localization.
• In vivo studies using murine embryonic meninges to evaluate cilia length and gene expression in Foxc1 mutants.

Main Results:

• Patients with FOXC1-related ARS exhibit a high prevalence of ciliopathy-associated phenotypes.
• Altering Foxc1 levels significantly modifies cilia length in vitro and in vivo.
• Foxc1 manipulation perturbs Hedgehog (Hh) and PDGFRα signaling pathways, including Gli2 compartmentalization.
• Foxc1 deficiency in murine meninges leads to reduced cilia length and dysregulated expression of Hh and Pdgfrα pathway components.

Conclusions:

• FOXC1 plays a critical role in regulating cilia length and function.
• Altered cilia-mediated signaling, particularly Hh and PDGFRα pathways, contributes to FOXC1-associated phenotypes.
• This study provides a mechanistic link between FOXC1, cilia dysfunction, and disease pathogenesis.