Translational Control of Neuronal Fate and Identity

Información del proyecto

TransNeuroFate

Identificador del acuerdo de subvención: 101044937

DOI

10.3030/101044937

Fecha de la firma de la CE 14 Julio 2022

Fecha de inicio 1 Enero 2023

Fecha de finalización 31 Diciembre 2027

Financiado con arreglo a

• European Research Council (ERC)

Coste total

€ 2 000 000,00

Aportación de la UE

€ 2 000 000,00

Coordinado por

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - TransNeuroFate (Translational Control of Neuronal Fate and Identity)

Período documentado: 2023-01-01 hasta 2025-06-30

Resumen del contexto y de los objetivos generales del proyecto

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.
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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

We are combining 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 (Aim 1); and ii) determine how tRNA repertoires (both at the transcriptional (Aim 2) and post-transcriptional levels (Aim 3)) are shaped to meet the specific translational needs of different cell types during corticogenesis. To date, we have optimized most of the techniques required to complete the project. We have generated several datasets that are currently analyzed and integrated to better understand the role of tRNAs in brain development. We have initiated the characterization of tRNA content in the developing murine cortex and identify dynamic pattern of transfer RNA expression over time in the developing cerebral cortex. We have also pursued our investigation of functional roles of tRNA modification during the corticogenesis. We provide the first evidence for physiological roles for the ADAT2/ADAT3 complex and tRNA deamination during the development of the mammalian cerebral cortex. We propose that a critical threshold of ADAT2/ADAT3 activity is necessary to support proper neuronal development. This raises important questions about the role of I34 tRNA modifications in supporting the protein demands during brain development.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

This project provides the first catalogues of tRNA pools during corticogenesis and describe the underlying regulatory mechanisms. This work sheds new light on fundamental questions in cell biology, and provide significant molecular insights into cortical neurogenesis in health and disease. It opens new questions: How do tRNA repertoires change in time in pathological scenarios? Which developmental processes are controlled by tRNAs? Which mRNAs are aberrantly translated in neuronal cells with perturbed tRNA pools? Answers to those questions are critical to interpret the pathological mechanisms that participate in the onset and the progression of neurological disorders