Projektbeschreibung
Bestimmung der neuronalen Vielfalt in der Großhirnrinde
Die Großhirnrinde ist die äußerste Schicht des Gehirns. Sie ist für das Erinnerungs-, Denk- und Lernvermögen verantwortlich und setzt sich aus unterschiedlichen Arten von Neuronen zusammen. Studien zum Ursprung dieser neuronalen Vielfalt haben die Rolle der translationalen Regulation unterstrichen. Das vom Europäischen Forschungsrat finanzierte Projekt TransNeuroFate konzentriert sich auf die Frage, inwieweit die Verfügbarkeit von reifer Transfer-RNS (tRNS) als Regulator der neuronalen Vielfalt fungiert. Sein Ziel ist es, herauszufinden, welche translationalen Programme die Bestimmung der neuronalen Linie in der Großhirnrinde während der Entwicklung beeinflussen. Die Ergebnisse werden ferner dazu beitragen, neurologische Entwicklungsstörungen besser zu verstehen.
Ziel
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.
Wissenschaftliches Gebiet
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-AG - HORIZON Action Grant Budget-BasedGastgebende Einrichtung
75654 Paris
Frankreich