PRE2023-Human organoids to understand inborn eye defects -PID2022-136831OB-I00

Microphthalmia and anophthalmia (MA) are two related examples of highly impairing congenital malformations. In these conditions, the eye is either much reduced in size or completely absent, often in association with additional brain defects caused by the lack of the peripheral input on the appropriate targeted regions of the brain. We propose to use human iPSC to generate organoids that reproduce the initial stages of human eye development and test the hypothesis that part of these inborn defects is caused by an abnormal development of the Retinal Pigmented Epithelium (RPE), which, in turn, preclude a normal morphogenesis of the eye. Mutations in two transcriptional regulators (OTX2 and YAP1) expressed in the RPE are responsible of a MA cases. We will reproduce these mutations in the iPSC derived organoids to address our hypothesis and follow in real time how defects arise. This study integrates in the long-standing interest of the lab in eye development and in past and recent finding related to RPE development (PMID: 36714981; 34545806; 34162866; 31318166; 30406103; 11493524).