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Primary cilia deficiency in neural crest cells causes Anterior Segment Dysgenesis

Céline Portal, View ORCID ProfilePeter Lwigale, View ORCID ProfilePanteleimon Rompolas, View ORCID ProfileCarlo Iomini
doi: https://doi.org/10.1101/752105
Céline Portal
Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
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Peter Lwigale
BioSciences Department, Rice University, Houston, TX, 77005, USA.
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Panteleimon Rompolas
Department of Dermatology, Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
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Carlo Iomini
Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
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  • For correspondence: ciomini1@jhmi.edu
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ABSTRACT

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.

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  • The authors have declared that no conflict of interest exists.

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Posted August 30, 2019.
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Primary cilia deficiency in neural crest cells causes Anterior Segment Dysgenesis
Céline Portal, Peter Lwigale, Panteleimon Rompolas, Carlo Iomini
bioRxiv 752105; doi: https://doi.org/10.1101/752105
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Primary cilia deficiency in neural crest cells causes Anterior Segment Dysgenesis
Céline Portal, Peter Lwigale, Panteleimon Rompolas, Carlo Iomini
bioRxiv 752105; doi: https://doi.org/10.1101/752105

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