Primary cilia deficiency in neural crest cells models Anterior Segment Dysgenesis in mouse

Abstract
Data availability
Article and author information
Metrics

Abstract

Defects affecting tissues of the anterior segment (AS) of the eye lead to a group of highly debilitating disorders called Anterior Segment Dysgenesis (ASD). Despite the identification of some causative genes, the pathogenesis of ASD remains unclear. Interestingly, several ciliopathies display conditions of the AS. Using conditional targeting of Ift88 with Wnt1-Cre, we show that primary cilia of neural crest cells (NCC), precursors of most AS structures, are indispensable for normal AS development and their ablation leads to ASD conditions including abnormal corneal dimensions, defective iridocorneal angle, reduced anterior chamber volume and corneal neovascularization. Mechanistically, NCC cilia ablation abolishes hedgehog (Hh) signaling in the periocular mesenchyme (POM) canonically activated by choroid-secreted Indian Hh, reduces proliferation of POM cells surrounding the retinal pigment epithelium and decreases the expression of Foxc1 and Pitx2, two transcription factors identified as major ASD causative genes. Thus, we uncovered a signaling axis linking cilia and ASD.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Individual data points are represented on the figures.

Article and author information

Author details

Céline Portal

Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, United States

Competing interests
The authors declare that no competing interests exist.
Panteleimos Rompolas

Department of Dermatology, Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Peter Lwigale

BioSciences Department, Rice University, Houston, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1799-4905
Carlo Iomini

Department of Ophthalmology, Wilmer Eye Institute; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, United States

For correspondence
ciomini1@jhmi.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6483-9540

Funding

NIH Office of the Director (EY022639)

Carlo Iomini

NIH Office of the Director (EY022158)

Peter Lwigale

NIH Office of the Director (EY030599)

Panteleimos Rompolas

Research to Prevent Blindness (Dolly Green Special Scholar Award)

Carlo Iomini

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal procedures were performed in accordance with the guidelines and approval of the Institutional Animal Care and Use Committee at Icahn School of Medicine at Mount Sinai (protocol number: 18-1561), at Johns Hopkins University (protocol number: MO19M122), and at the University of Pennsylvania (protocol number: 805830).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.