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
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
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.
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.
Organisations
Publications
Clifton N
(2022)
Developmental disruption to the cortical transcriptome and synaptosome in a model of SETD1A loss-of-function
in Human Molecular Genetics
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 |
Description | MRC NMGN science meeting: Setd1a mutant mice reveal novel physiological and molecular pathways underpinning schizophrenia |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Gave a talk entitled "Setd1a mutant mice reveal novel physiological and molecular pathways underpinning schizophrenia" at the MRC NMGN science day in York |
Year(s) Of Engagement Activity | 2024 |
Description | Psychiatry Consortium targets workshop |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Psychiatry Consortium organised a workshop to discuss possible therapeutic targets for neuropsychiatric disorders - Setd1a was one of the targets and I was invited because of my expertise in this area and in preclinical models more generally |
Year(s) Of Engagement Activity | 2022 |