Role of ciliopathy protein TMEM107 in eye development: insights from a mouse model and retinal organoid

Abstract

Primary cilia are cellular surface projections enriched in receptors and signaling molecules, acting as signaling hubs that respond to stimuli. Malfunctions in primary cilia have been linked to human diseases, including retinopathies and ocular defects. Here, we focus on TMEM107, a protein localized to the transition zone of primary cilia. TMEM107 mutations were found in patients with Joubert and Meckel–Gruber syndromes. A mouse model lackingTmem107exhibited eye defects such as anophthalmia and microphthalmia, affecting retina differentiation.Tmem107expression during prenatal mouse development correlated with phenotype occurrence, with enhanced expression in differentiating retina and optic stalk. TMEM107 deficiency in retinal organoids resulted in the loss of primary cilia, down-regulation of retina-specific genes, and cyst formation. Knocking out TMEM107 in human ARPE-19 cells prevented primary cilia formation and impaired response toSmoothenedagonist treatment because of ectopic activation of the SHH pathway. Our data suggest TMEM107 plays a crucial role in early vertebrate eye development and ciliogenesis in the differentiating retina.

Classical and Innovative Evidence for Therapeutic Strategies in Retinal Dysfunctions

“…Because of their characteristics, organoids can be defined as cultures that exhibit multi-cellularity and functionality, show spatial architecture like in vivo organs, and preserve stem cells or progenitor pools [198]. Since 2009, when for the first time a small intestinal organoid was established in vitro [199], several 3D cultures were obtained from different organs, such as the kidney [200,201], liver [202,203], brain [204,205], and retina [206,207], by changing the combination of growth factors and cell isolation procedures. The organoids can be classified into three types, based on different characteristics, such as types of cells and how they interact with each other: they are classified as epithelial, multi-tissue, and multiorgan [208].…”