IMPC: Investigating the brain role of Setd1a in relation to schizophrenia and developmental disorders

Lead Research Organisation: Cardiff University
Department Name: School of Medicine

Abstract

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Technical Summary

Many psychiatric disorders are, in part, heritable. Genetic studies of these psychiatric disorders are providing valid leads to investigate their biology, with the hope that this may one day lead to therapies. Genetic risk for many mental disorders divides into a large number of common
variants that have very small, but cumulative effects; and several very rare, damaging variants. Recent technological advances have allowed us to identify rare genetic mutations that have strong consequences for complex brain diseases. Member of the MRC Centre for Neuropsychiatric
Genetics and Genomics in Cardiff (CNGG) were part of an international team that identified such a rare mutation contributing to schizophrenia and other developmental disorders in a gene called SET domain 1a (SETD1A). SETD1A encodes an enzyme that can regulate the activity of other genes. However, the specific brain functions of this gene remain unknown. We want to examine what SETD1A does through replicating the mutation in a mouse model by removing one of the two copies of this gene in the mouse genome. However, we will limit this genetic mutation to the brain, in order to clearly examine the role SETD1A plays in the brain. This grant will help us to generate and develop this mouse model, and to start the early characterisation.

Publications

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Title Generated a tm1d constitutive Setd1a knockout mouse model 
Description By crossing our Tm1c Setd1a conditional ready knockout model to a CMV-cre (a ubiquitous cre-line) we were able to generate a full (constitutive) Setd1a knockout mouse line free from the targeting construct and markers (such as LacZ) 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2019 
Provided To Others? Yes  
Impact None as yet 
 
Title Generation of conditional-ready (Tm1c) Setd1a knockout 
Description A conditional-ready (Tm1c) knockout mouse model of the schizophrenia and developmental delay gene, Setd1a 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2017 
Provided To Others? Yes  
Impact This model allows us and other researchers to generate region specific knockouts of this key schizophrenia and developmental delay gene 
 
Title Setd1a-nestin-cre knockout 
Description A knockout of the schizophrenia and developmental delay gene Setd1a limited to nestin expressing cells only. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2018 
Provided To Others? Yes  
Impact Allows behavioural assessment of thisschizophrenia and developmental delay gene 
 
Description FENS 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact PhD student Matt Bosworth attended and presented a poster at FENS 2018 in Berlin, Germany
Year(s) Of Engagement Activity 2018
 
Description FENS2020 - Bosworth 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Poster presentation at FENS 2020 - Matthew Bosworth
Year(s) Of Engagement Activity 2020