PUBLICATION

Mitochondrial proteins encoded by the 22q11.2 neurodevelopmental locus regulate neural stem and progenitor cell proliferation

Authors
Campbell, P.D., Lee, I., Thyme, S., Granato, M.
ID
ZDB-PUB-231005-65
Date
2023
Source
Molecular psychiatry   28(9): 3769-3781 (Journal)
Registered Authors
Campbell, Philip, Granato, Michael
Keywords
none
MeSH Terms
  • DiGeorge Syndrome*/genetics
  • DiGeorge Syndrome*/pathology
  • Brain/pathology
  • Zebrafish
  • Mitochondrial Proteins
  • Schizophrenia*/genetics
  • Animals
  • Humans
(all 8)
PubMed
37794116 Full text @ Mol. Psychiatry
Abstract
Microdeletion of a 3Mb region encompassing 45 protein-coding genes at chromosome 22q11.2 (22q11.2DS) predisposes individuals to multiple neurodevelopmental disorders and is one of the greatest genetic risk factors for schizophrenia. Defective mitochondrial function has been hypothesized to contribute to 22q11.2DS pathogenesis; however, which of the six mitochondrial genes contribute to neurodevelopmental phenotypes and their underlying mechanisms remain unresolved. To systematically test 22q11.2DS genes for functional roles in neurodevelopment and behavior, we generated genetic mutants for each of the 37 conserved zebrafish orthologs and performed high throughput behavioral phenotyping using seven behavioral assays. Through this unbiased approach, we identified five single-gene mutants with partially overlapping behavioral phenotypes. Two of these genes, mrpl40 and prodha, encode for mitochondrial proteins and, similar to what we observed in mrpl40 and prodha mutants, pharmacologic inhibition of mitochondrial function during development results in microcephaly. Single mutant analysis shows that both mrpl40 and prodha mutants display aberrant neural stem and progenitor cell proliferation, with each gene regulating distinct cell populations. Finally, double mutants for both mrpl40 and prodha display aggravated behavioral phenotypes and neural stem and progenitor cell analysis reveals a previously unrecognized partially redundant role for mrpl40 and prodha in regulating radial glia-like cell proliferation. Combined, our results demonstrate a critical role for mitochondrial function in neural stem and progenitor cell populations in the developing vertebrate brain and provide compelling evidence that mitochondrial dysfunction during neurodevelopment is linked to brain volume and behavioral phenotypes observed in models of 22q11.2DS.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
p434
    		Small Deletion
    p435
      		Indel
      p436
        		Small Deletion
        p437
          		Small Deletion
          p438
            		Small Deletion
            stl84TgTransgenic Insertion
              vo80TgTransgenic Insertion
                zf148TgTransgenic Insertion
                  1 - 8 of 8
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                  Human Disease / Model
                  No data available
                  Sequence Targeting Reagents
                  No data available
                  Fish
                  No data available
                  Antibodies
                  Name Type Antigen Genes Isotypes Host Organism
                  Ab1-casp3monoclonal
                    		IgGRabbit
                    Ab2-pcnamonoclonalIgG2aMouse
                    Ab3-sox2polyclonalIgGRabbit
                    Ab4-h3polyclonal
                      		IgGRabbit
                      Ab12-mapkmonoclonal
                        		IgG1Mouse
                        1 - 5 of 5
                        Show
                        Orthology
                        No data available
                        Engineered Foreign Genes
                        Marker Marker Type Name
                        DsRedEFGDsRed
                        GFPEFGGFP
                        mCherryEFGmCherry
                        sfGFPEFGsfGFP
                        1 - 4 of 4
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                        Mapping
                        No data available
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                        Citation
                        Campbell, P.D., Lee, I., Thyme, S., Granato, M. (2023) Mitochondrial proteins encoded by the 22q11.2 neurodevelopmental locus regulate neural stem and progenitor cell proliferation. Molecular psychiatry. 28(9):3769-3781.