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Carlo Iomini, Laura Grisanti, Qing Liu; Anterior Segment Dysgenesis (ASD) disorders in a ciliopathy mouse model. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1997.
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© ARVO (1962-2015); The Authors (2016-present)
ASD represents one of the main causes of congenital corneal opacity, and leads to glaucoma in ~50% of the cases. Although, few causative genes have been identified, little is known about the molecular and cellular mechanisms underlying tissue malformation in this class of disease. Several ciliopathies including Meckel, Bardet Biedl and Joubert syndromes display conditions affecting tissue of the AS. Here we investigate the role of cilia during development of the AS in mice.
Phenotypic analysis of the AS in conditional ciliary mutants was performed using light and transmission electron microscopy. Genes expression in AS tissues was assessed by using qRT-PCR and immunostaining approaches and using reporter mouse lines. Cell proliferation of periocular mesenchyme (POM) was assessed by BrdU incorporation and immunostaining.
Null mutations that prevent cilia assembly such as Ift88-/- are lethal at E9.5-10.5. In Ift88-/- embryos the optic vesicle, although defective, is present. In contrast, the optic cup observed in wild-type embryos at E10.5 does not form. To overcome mid-gestation lethality generated a conditional KO mouse Wnt1-Cre;IFT88flox/- (cKO) in which the Ift88 gene is excised in all migrating POM cells of neural crest origin. CKO mice display strong craniofacial defects and die at birth (P0). Early eye patterning appears normal. However, later in development cKO mice display significant reduction of the anterior chamber a thinner stromal ECM and corneal endothelial malformations. Interestingly, although migration of neural crest-derived cells appears normal, we detected reduction of mesenchymal cells at the angle between the stroma and the optic cup at E17.5. Mechanistically, we found that the Hedgehog (Hh) signaling and cell proliferation were impaired in a subpopulation of POM cells surrounding the optic nerve, the retinal pigment epithelium up to the iridocorneal angle of cKO mice. Gene expression analysis confirmed disruption of the Hedgehog pathway and revealed reduction Ptx2 but not Foxc1, both encoding for transcription factors linked to the Axenfeld-Rieger Syndrome.
We have uncovered a pivotal role of primary cilia in the development of the AS and highlighted their involvement in the etiology of ocular disorders derived from ASD.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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