Under the supervision of Valérie Dupé

Presentation summary:

The development of the human brain is an intricate and fascinating process, and understanding it is essential for addressing the challenges posed by neurodevelopmental disorders. In the GeDiNe research team, my thesis focused on the mechanisms involved in the formation of the forebrain, with a particular emphasis on the role of the Sonic Hedgehog (SHH) signaling pathway in the regionalization and morphogenesis of neuroectodermal tissue, which is crucial for forebrain formation. This work contributes to ongoing research on holoprosencephaly (HPE), a brain malformation linked to disruptions in the SHH pathway.
HPE is a rare condition with a wide phenotypic spectrum, and its genetic causes remain complex and largely unknown. Currently, only 30% of HPE patients receive a molecular diagnosis. To address this gap, my thesis aimed to develop in vitro models based on induced pluripotent stem cells (iPSCs) to further investigate the role of SHH in this disease. I successfully established a model for differentiating iPSCs into ventral anterior neuroectoderm, the primary tissue affected in HPE.
Through this model, I demonstrated how inhibition of the SHH pathway influences the development of ventral and dorsal forebrain tissues. Transcriptomic analyses provided detailed molecular profiles of healthy and SHH-deregulated tissues, uncovering new potential SHH target genes that could serve as biomarkers for HPE. Additionally, CRISPR/Cas9 technology was used to validate these targets in a genetic model of the disease.
In summary, this thesis represents a significant advancement in HPE modeling by introducing an innovative approach to studying the mechanisms of the SHH pathway. The findings have the potential to improve molecular diagnostics and facilitate the development of predictive tools for better clinical management of HPE patients.

Composition of the jury:

• Alexandre Baffet - Institut Curie - Paris
• Marion Delous - Lyon 1 University
• Frédéric Laumonnier - Tours University
• Frédéric Chalmel - IRSET, Rennes
• Valérie Dupé - Inserm, IGDR Rennes
• Marie De Tayrac - CHU de Rennes, IGDR