Translational Control of Neuronal Fate and Identity

Introduction

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 understanding how cortical architecture and functions emerge during development and remains a critical challenge in cellular and molecular neurobiology.

Translational Control Hypothesis

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.

Functional Link Between Development and tRNAs

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.

Research Objectives

Studying this yet unexplored question should unravel a hitherto unrecognized level of neuronal fate identity determination in the cerebral cortex. We will combine:

1. Ribosome profiling
2. mRNA and tRNA deep sequencing
3. Screening of genetic perturbation and gene manipulation in vivo in the mouse embryonic cortex

Specific Aims

The specific aims of this project are to:

i. Uncover the specific translational programs that influence neuronal lineage 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;
iii. Validate the functional importance of fluctuation in mature tRNA content during cortical development.

Expected Outcomes

This project should bring conceptual advances in the understanding of brain development mechanisms that could be instrumental in interpreting the pathological mechanisms of neurodevelopmental disorders.