Primary cilia deficiency in neural crest cells models anterior segment dysgenesis in mouse.

Céline Portal,Peter Lwigale,Carlo Iomini,Panteleimos Rompolas

doi:10.7554/elife.52423

Céline Portal, Peter Lwigale + Show 2 more

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https://doi.org/10.7554/elife.52423

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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.

Highlights

Anterior segment dysgenesis (ASD) is a term referring to a spectrum of congenital disorders of structures of the anterior segment (AS) of the eye
neural crest cells (NCC) were traced by using the Rosa26mT/membrane-targeted green fluorescent protein (mG) reporter mouse line [44] crossed to the Wnt1-Cre mouse [45] in which the Cre recombinase is under the control of the Wnt1 promoter, a gene highly expressed in early stages of NCC specification
Our previous studies reported that while primary cilia are present in developing corneal endothelium, they disassemble in adult corneal endothelium at steady state [46]

Summary

Introduction

Anterior segment dysgenesis (ASD) is a term referring to a spectrum of congenital disorders of structures of the anterior segment (AS) of the eye. Most AS structures are derived from the neural crest cells (NCC), including the corneal stroma and endothelium, ciliary body muscle and body, iris stroma, and the trabecular meshwork [5]. In mice, migrating NCC of the periocular mesenchyme (POM) begin to invade the AS of the eye between E11.5 and E12.5, and differentiate into corneal endothelial cells and keratocytes[6, 7]. The neural crest is a transient embryonic structure in vertebrates that delaminates from the border between the neural plate and the non-neural ectoderm; NCC migrate throughout the embryo to multiple locations and differentiate into a wide variety of cell types and tissues [10, 11]. Recent studies have shown that primary cilia play essential roles in morphogenetic processes involving neural crest-derived cells such as craniofacial development [12, 13]. It has been proposed that primary cilia seem to mediate tissue-tissue interactions requiring reciprocal signaling rather than purely NCC specification [14, 15]

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