Mots-Clés

Neurodevelopmental disorders, Heat Shock Factors, human cortical organoids, single-cell

Description

Neurodevelopmental disorders (NDDs) affect 10% of children, causing lifelong cognitive and behavioral
challenges. The clinical variability of NDDs complicates the search for effective treatments. Our project
targets a common feature across NDDs: disruption of stress response pathways, specifically involving Heat
Shock Factors (HSFs). HSF2, which regulates proteostasis during stress, also plays a key role in brain
development under normal conditions. Using two patient-derived iPSC models of NDDs—both exhibiting
HSF2 dysregulation—and their isogenic models with restored HSF2, we aim to pinpoint the specific role of
the HSF pathway in NDDs. Through advanced single-cell analyses applied to cerebral organoids derived from
these models, we will identify HSF-dependent genes, pathways, and cell populations. These discoveries will
be validated through independent approaches and will serve as a “readout” for future drug screening.

The candidate will develop the NDD model (Angelman-like syndrome, AGS-L) by generating patient hCOs and
HSF2-rescued patient hCOs (done by genome editing), then conduct a sc-MO comparative analysis of HSF2-
rescued and patient hCOs at two developmental stages. Finally, he will validate the defective molecular
pathways identified in hCOs, focusing on stress and adhesion related pathways. Combining results from the
RSTS model and the established AGS-L model will shed light on the core defective pathways dependent on
HSF2.