Description du projet
Déterminer la diversité neuronale du cortex cérébral
Le cortex cérébral est la couche externe du cerveau. Il est responsable de la mémoire, de la pensée et de l’apprentissage et se compose de divers types de neurones. L’étude de l’origine de cette diversité neuronale a mis en évidence un rôle dans la régulation translationnelle. Financé par le Conseil européen de la recherche (CER), le projet TransNeuroFate se concentre sur la manière dont la disponibilité des ARN de transfert (ARNt) matures constitue un régulateur de la diversité neuronale. L’idée est d’étudier quels programmes translationnels influencent la détermination du lignage neuronal dans le cortex cérébral au cours du développement. Les résultats permettront également d’interpréter les troubles du développement neurologique.
Objectif
The cerebral cortex is a central structure of the mammalian brain, characterized by a remarkable diversity of neuronal types. Understanding the origin of the extraordinary neuronal diversity is fundamental to understand how cortical architecture and functions emerge during development and remains a critical challenge in cellular and molecular neurobiology.
While the efforts have been focused on transcriptional control, evidence for regulation at the translational level is emerging. I hypothesize that translational control, albeit overlooked, acts in a combinatorial fashion with transcriptional induction to regulate gene expression programs during cortical patterning. I have demonstrated an intimate functional link between cortical development and pools of mature transfer RNA (tRNAs), the major determinant of translation. I, therefore, propose to address how translational control, through the modulation of the availability of mature translationally competent tRNAs, fine-tunes gene expression programs during lineage progression, thereby regulating neuronal diversity. Studying this yet unexplored question should unravel a hitherto unrecognized level of neuronal fate identity determination in the cerebral cortex.
We will combine ribosome profiling, mRNA and tRNA deep sequencing, screening of genetic perturbation and gene manipulation in vivo in the mouse embryonic cortex to i) uncover the specific translational programs that influence neuronal lineages progression; ii) determine how tRNA repertoires (both at the transcriptional and post-transcriptional levels) are shaped to meet the specific translational needs of different cell types during corticogenesis and iii) validate the functional importance of fluctuation in mature tRNA content during cortical development.
This project should bring conceptual advances in the understanding of brain development mechanisms that could be instrumental to interpret the pathological mechanisms of neurodevelopmental disorders.
Champ scientifique
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régime de financement
HORIZON-AG - HORIZON Action Grant Budget-BasedInstitution d’accueil
75654 Paris
France