PT  - JOURNAL ARTICLE
AU  - Céline Portal
AU  - Peter Lwigale
AU  - Panteleimon Rompolas
AU  - Carlo Iomini
TI  - Primary cilia deficiency in neural crest cells causes Anterior Segment Dysgenesis
AID  - 10.1101/752105
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 752105
4099  - http://biorxiv.org/content/early/2019/08/30/752105.short
4100  - http://biorxiv.org/content/early/2019/08/30/752105.full
AB  - During eye embryogenesis, neural crest cells (NCC) of the periocular mesenchyme (POM) migrate to the anterior segment (AS) of the eye and then differentiate into the corneal stroma and endothelium, ciliary body, iris stroma, and the trabecular meshwork. Defective development of these structures leads to anterior segment dysgenesis (ASD) that in 50% of the cases leads to glaucoma, a leading cause of blindness. Here, we show that the primary cilium is indispensable for normal AS development and that its ablation in NCC induces ASD phenotypes including; small and thin cornea, impaired stromal keratocyte organization, abnormal iridocorneal angle with reduced anterior chamber and corneal neovascularization. These defects are similar to those described in patients with AS conditions such as Axenfeld-Rieger syndrome and Peter’s anomaly. Mechanistically, disruption of the primary cilium in the NCC resulted in reduced hedgehog (Hh) signaling in the POM, canonically activated by the Indian Hedgehog ligand expressed by endothelial cells of the choroid. This caused decreased cell proliferation in a subpopulation of POM cells surrounding the retinal pigmented epithelium. Moreover, primary cilium ablation in NCC also led to a decreased expression of Foxc1 and Pitx2, two transcription factors identified as major ASD causative genes. These findings suggest that primary cilia are indispensable for NCC to form normal AS structures via Hh signaling. Defects in primary cilia could, therefore, contribute to the pathogenesis of ASD, and to their complications such as congenital glaucoma.