Modeling neurodevelopmental disorders using induced stem cells and cerebral organoids: the example of Mediator-related disorders – NDevCerebrOids

Neurodevelopmental disorders (NDDs) are child related diseases that include intellectual deficiency (ID), autism spectrum disorders (ASD) and epilepsy. Their molecular diagnosis has been considerably improved in the recent years. However, appropriate experimental models for functional studies are still missing. The recent development of cerebral organoid models from human stem cells or induced pluripotent stem cells (iPSCs) offers new opportunities.
Here, we suggest to combine a 3D cellular model to the traditional 2D culture to model Mediator related NDDs that are caused by mutations in a gene encoding for one of the subunits composing the Mediator complex (MED). Affected patients display ID of variable severity that may be associated with ASD, epilepsy or other congenital malformations. MED is essential for PolII transcription and functional enhancer-promoter interactions but its role in early brain development and the mechanisms leading to NDD in case of a mutation remain to be deciphered.
This project aims at: 1. developing a relevant experimental model for the study of NDDs of genetic origin, 2. understanding the role of MED in neuronal differentiation and early brain development and how mutations in MED genes lead to NDDs, 3. exploring the impact of the genetic background on phenotype variability.
We will introduce a set of MED mutations that we identified in our cohort of NDD patients into isogenic hiPSCs to analyze the sole effect of MED mutations and ensure a successful generation of organoids. We will analyze their impact on cell phenotype, transcription in link with chromatin state at genes and distal elements, as well as the impact on MED structure and MED-PolII interactions. Phenotypic alterations will be then studied in models generated using iPSC derived from the NDD patients carrying these mutations to validate our results on isogenic cells and investigate the impact of the the genetic background on the phenotype expression variability.
This project will generate results that are crucial to understand the mechanisms of NDDs and a powerful tool for their study.