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The Role of Translational Control in Cortical Dysgenesis in Mammalian Brain

Project Overview

Abnormal development of neural circuitry is thought to be the major cause of autism and many other mental illnesses. However, we still don’t understand the cellular mechanisms that result in these alterations, and the underlying genetic and/or environmental causes are still unclear. In this regard, recent evidence from the Miller laboratory has shown that mutations in pathways regulating the development of neural precursor cells (NPCs), which give birth to various types of neurons, contribute to cognitive deficits in disorders that cause intellectual disability1,2 . These findings raise the possibility that disturbed development of embryonic NPCs may also contribute to cognitive abnormalities in other mental health disorders such as autism spectrum disorder (ASD) by deregulating neurogenesis. To explore this possibility, I screened a pool of autism candidate genes from human association studies, and identified 15 genes that are expressed in NPCs and enriched at the embryonic ventricular zone, where NPCs reside. Intriguingly, two of these genes are implicated in local translational control; the eukaryotic initiation factor 4e (EIF4e), which is the rate limiting factor for almost all mRNA translation in mammals, and the cytoplasmic FMR interacting protein-1 (CYFIP1), which has been recently identified as a suppressor for EIF4e in adult mouse neurons6 . Since recent work from the Miller laboratory on the RNA-binding protein Staufen2 has identified an important role for localized mRNA translation in NPC fate determination3 , I have hypothesized that perturbations in translational regulation in NPCs caused by mutations in EIF4e and CYFIP1 contribute to ASD. Here, I will test this hypothesis, and will ask how translational control mediated by these two proteins contributes to NPC development.

Principal Investigator

Guang Yang , The Hospital For Sick Children

Partners and Donors

Bell Canada

Project Complete

The Role of Translational Control in Cortical Dysgenesis in Mammalian Brain

  • Program Type

    Capacity building grants

  • Area of research

    Neurodevelopment

  • Disease Area

    Autism

  • Competition

    Bell Mental Health Research Training Awards

  • Province

    Ontario

  • Start Date

    2013

  • Total Grant Amount

    $165,000

  • Health Canada Contribution

    $82,500