Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome
Open accessAbstract
The 22q11 deletion (or DiGeorge) syndrome (22q11DS), the result of a 1.5- to 3-megabase hemizygous deletion on human chromosome 22, results in dramatically increased susceptibility for “diseases of cortical connectivity” thought to arise during development, including schizophrenia and autism. We show that diminished dosage of the genes deleted in the 1.5-megabase 22q11 minimal critical deleted region in a mouse model of 22q11DS specifically compromises neurogenesis and subsequent differentiation in the cerebral cortex. Proliferation of basal, but not apical, progenitors is disrupted, and subsequently, the frequency of layer 2/3, but not layer 5/6, projection neurons is altered. This change is paralleled by aberrant distribution of parvalbumin-labeled interneurons in upper and lower cortical layers. Deletion of Tbx1 or Prodh (22q11 genes independently associated with 22q11DS phenotypes) does not similarly disrupt basal progenitors. However, expression analysis implicates additional 22q11 genes that are selectively expressed in cortical precursors. Thus, diminished 22q11 gene dosage disrupts cortical neurogenesis and interneuron migration. Such developmental disruption may alter cortical circuitry and establish vulnerability for developmental disorders, including schizophrenia and autism.
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Gene sets involved in cell and neuronal development and function (including projection, motility and proliferation) previously reported in ASD-associated phenotypes were identified.
“For example, gene sets involved in cell and neuronal development and function (including projection, motility and proliferation) previously reported in ASD-associated phenotypes were identified 24 .”
From Functional impact of global rare copy number variation in autism spectrum disorders (2010) · cites this paper as [24]
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“In addition, Tbx1, Cerebral Cortex October 2015, V 25 N 10 3299 another T-box gene that has been described to affect proliferation of IPCs is correlated with DiGeorge Syndrome (Meechan et al. 2009) leading to a decrease in supragranular layer neurons.”
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- Authors
- Meechan, D. W., Tucker, E. S., Maynard, T. M., & LaMantia, A.-S.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Department of Cell and Molecular Physiology and
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-09-22
- Volume
- 106
- Issue
- 38
- Pages
- 16434-16445
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2752572
- OpenAlex
- W1985400815
- Cited by
- 173
- References
- 54
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 2 · 2023: 11 · 2022: 6 · 2021: 6 · 2020: 12 · 2019: 8 · 2018: 3 · 2017: 10 · 2016: 10 · 2015: 9 · 2014: 13 · 2013: 25 · 2012: 13
- FWCI
- 4.39
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institute of Mental Health (MH-64065, P50MH064065)
- National Institute of Neurological Disorders and Stroke (NS-031768, R01NS031768)
- National Institute of Child Health and Human Development (HD042182)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD029178, R01HD029178, R29HD029178, R01HD042182, HD042182)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- 22q11.2 deletion syndrome, neurogenesis, cortical development, gene dosage, basal progenitors, apical progenitors, projection neurons, interneuron migration, parvalbumin interneurons, cortical layers, Tbx1, proline dehydrogenase, schizophrenia, autism spectrum disorder, mouse model
- MeSH terms
- Animals, Cell Differentiation, Cerebral Cortex, Chromosome Deletion, Chromosomes, Human, Pair 21, DiGeorge Syndrome, Disease Models, Animal, Histones, Humans, Immunohistochemistry, Mice, Inbred C57BL, Phosphoproteins, Mice, Knockout, Gene Expression Regulation, Developmental, Cell Cycle Proteins, Cyclin D1, Reverse Transcriptase Polymerase Chain Reaction, T-Box Domain Proteins, Synteny, Chromosomes, Mammalian, Cell Proliferation, Mice
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