Grant: Operating Grant: SickKids-CIHR-IHDCYH New Investigator Grants

Research Institute of the McGill University Health Centre

$279,560.00

Determine how somatic gene deletion causes disordered childhood brain development

FY 2020-21

Summary

Autism Spectrum Disorders (ASDs) affect 1 in 66 children in Canada, posing a tremendous mental healthburden. Mosaic genetic deletion has emerged as a prominent cause for ASDs. Mosaic mutations onlyaffect a small portion of cells in the brain, but often cause symptoms similar to those caused bygermline genetic mutations. This suggests that isolated mutant cells affect the development and/orfunction of the surrounding healthy cells. Mosaic deletions of Retinoic Acid Induced 1 (RAI1, encoding achromatin-binding protein), is responsible for a syndromic ASD called Smith-Magenis Syndrome (SMS).This proposal will use a new mouse model of mosaic Rai1 deletion to elucidate the non-cell autonomousmechanism by which mosaic Rai1 loss drives neural dysfunction in SMS. Morphological and functional deficits in cerebellum are the most consistent findings in ASD patients. Inunpublished data, we discovered that in the cerebellum, Rai1 is expressed in the Bergmann glia but notPurkinje cells, the principle neurons of cerebellum. Our newly developed mosaic Rai1 deletion mousemodel shows decreased Bergmann glia gliogenesis and severe dendritic arborization defects of Purkinjecells. Our data suggest a non-cell autonomous role for glial Rai1 in cerebellar neuronal development.This study will determine the molecular and cellular mechanism by which mosaic Rai1 deletion affectsBergmann glia development and Purkinje cell dendritic defects. We will also determine if mosaic Rai1deletion causes SMS-like neurobehavioral defects. We anticipate that our work will uncover a novelmechanism that drives pathogenesis of mosaic ASDs, which may help to shed light on the etiology andtherapeutic interventions of this complex childhood disorder. The support from Sickkids foundation willalso help us raise awareness for children suffer from mosaic genetic disorders, which are often under-diagnosed.

Department

Canadian Institutes of Health Research

Program

Operating Grant: SickKids-CIHR-IHDCYH New Investigator Grants

Recipient

Research Institute of the McGill University Health Centre

Location

Quebec, Canada

Type

Grant

Source

CIHR Funding Decisions Database

As published

438783

Name

Huang Wei-Hsiang

Region

Québec

Country

Canada

Orgtype

Institution Paid; Research Institution

Prcname2

Special Cases

Projecttitle

Determine how somatic gene deletion causes disordered childhood brain development

Programtype2

Operating Grants

Orgnameinp2

Research Institute of the McGill University Health Centre

Cihramount2

$279,560

Cihrequipment2

Programname2

Operating Grant: SickKids-CIHR-IHDCYH New Investigator Grants

Keyworddelim

Competitiondate

202007

Approvedterm2

3 yrs 0 mth

Pinamesdelim

Huang, Wei-Hsiang

Approvedterm

3 ans 0 mois

Cihrcontribution2

Inst of Human Dev &Child &Yth~ $279,560~ $0~

Abstract

<html> <head> </head> <body> Autism Spectrum Disorders (ASDs) affect 1 in 66 children in Canada, posing a tremendous mental healthburden. Mosaic genetic deletion has emerged as a prominent cause for ASDs. Mosaic mutations onlyaffect a small portion of cells in the brain, but often cause symptoms similar to those caused bygermline genetic mutations. This suggests that isolated mutant cells affect the development and/orfunction of the surrounding healthy cells. Mosaic deletions of Retinoic Acid Induced 1 (RAI1, encoding achromatin-binding protein), is responsible for a syndromic ASD called Smith-Magenis Syndrome (SMS).This proposal will use a new mouse model of mosaic Rai1 deletion to elucidate the non-cell autonomousmechanism by which mosaic Rai1 loss drives neural dysfunction in SMS. Morphological and functional deficits in cerebellum are the most consistent findings in ASD patients. Inunpublished data, we discovered that in the cerebellum, Rai1 is expressed in the Bergmann glia but notPurkinje cells, the principle neurons of cerebellum. Our newly developed mosaic Rai1 deletion mousemodel shows decreased Bergmann glia gliogenesis and severe dendritic arborization defects of Purkinjecells. Our data suggest a non-cell autonomous role for glial Rai1 in cerebellar neuronal development.This study will determine the molecular and cellular mechanism by which mosaic Rai1 deletion affectsBergmann glia development and Purkinje cell dendritic defects. We will also determine if mosaic Rai1deletion causes SMS-like neurobehavioral defects. We anticipate that our work will uncover a novelmechanism that drives pathogenesis of mosaic ASDs, which may help to shed light on the etiology andtherapeutic interventions of this complex childhood disorder. The support from Sickkids foundation willalso help us raise awareness for children suffer from mosaic genetic disorders, which are often under-diagnosed. </body> </html>

View source data CIHR Funding Decisions Database (Canadian Institutes of Health Research)