Linking spatial gene expression patterns to sex-specific brain structural changes on a mouse model of 16p11.2 hemideletion
Open accessAbstract
Neurodevelopmental disorders, such as ASD and ADHD, affect males about three to four times more often than females. 16p11.2 hemideletion is a copy number variation that is highly associated with neurodevelopmental disorders. Previous work from our lab has shown that a mouse model of 16p11.2 hemideletion (del/+) exhibits male-specific behavioral phenotypes. We, therefore, aimed to investigate with magnetic resonance imaging (MRI), whether del/+ animals also exhibited a sex-specific neuroanatomical endophenotype. Using the Allen Mouse Brain Atlas, we analyzed the expression patterns of the 27 genes within the 16p11.2 region to identify which gene expression patterns spatially overlapped with brain structural changes. MRI was performed ex vivo and the resulting images were analyzed using Voxel-based morphometry for T1-weighted sequences and tract-based spatial statistics for diffusion-weighted images. In a subsequent step, all available in situ hybridization (ISH) maps of the genes involved in the 16p11.2 hemideletion were aligned to Waxholm space and clusters obtained by sex-specific group comparisons were analyzed to determine which gene(s) showed the highest expression in these regions. We found pronounced sex-specific changes in male animals with increased fractional anisotropy in medial fiber tracts, especially in those proximate to the striatum. Moreover, we were able to identify gene expression patterns spatially overlapping with male-specific structural changes that were associated with neurite outgrowth and the MAPK pathway. Of note, previous molecular studies have found convergent changes that point to a sex-specific dysregulation of MAPK signaling. This convergent evidence supports the idea that ISH maps can be used to meaningfully analyze imaging data sets.
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The human 16p11.2 locus is a roughly 500-600 kb region containing 27-29 genes on the proximal short arm of chromosome 16.
“The human 16p11.2 gene locus (chromosome 16, position 11.2) is a ~500–600 kb region containing 27–29 genes [4–7] located on the proximal short arm of chromosome 16 [8].”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [7]
In the 16p11.2 hemideletion mouse model, gray matter volume does not differ from controls.
“16p11.2+/− mice (Mills) do not exhibit changes in gray matter [7]”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [7]
The same hemideletion mice show increases in medial and peristriatal fiber tracts that are specific to males.
“they show male-specific increases in medial and peristriatal fiber tracts [7]”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [7]
The medial fiber tract increase in 16p11.2 hemideletion mice matches the increase seen in human deletion carriers.
“but they show male-specific increases in medial and peristriatal fiber tracts [7], coinciding with the increased medial fiber tracts in human deletion carriers [14]”
From 16p11.2 Copy Number Variations and Neurodevelopmental Disorders (2020) · cites this paper as [7]
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References 96 · Cited by 54
- Authors
- Kumar, V. J., Grissom, N. M., McKee, S. E., Schoch, H., Bowman, N., Havekes, R., Kumar, M., Pickup, S., Poptani, H., Reyes, T. M., Hawrylycz, M., Abel, T., & Nickl-Jockschat, T.
- Affiliations
- Max Planck Institute for Biological Cybernetics (DE)
- University of Minnesota (US)
- University of Pennsylvania (US)
- University of Groningen (NL)
- University of Liverpool (GB)
- University of Cincinnati (US)
- Allen Institute for Brain Science (US)
- University of Iowa (US)
- ORCID
- Venue
- Translational Psychiatry
- Published
- 2018-05-29
- Volume
- 8
- Issue
- 1
- Pages
- 109-109
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC5974415
- OpenAlex
- W2805189754
- Cited by
- 54
- References
- 96
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 10 · 2022: 6 · 2021: 10 · 2020: 6 · 2019: 6 · 2018: 3
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by)
- RWTH Publications (RWTH Aachen) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- RWTH Publications (RWTH Aachen)
- Funders
- National Institute of Environmental Health Sciences (T32ES019851, P30ES013508)
- Topics
- 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
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- sex differences, neurodevelopmental disorders, copy number variation, mouse model, brain structural changes, gene expression patterns, white matter anisotropy, striatum, neurite outgrowth, MAPK signaling, autism spectrum disorder, attention deficit hyperactivity disorder
- MeSH terms
- Animals, Autistic Disorder, Chromosome Deletion, Chromosomes, Human, Pair 16, Disease Models, Animal, Female, Humans, Male, Intellectual Disability, Mice, Inbred C57BL, Gene Expression, In Situ Hybridization, Mice, Knockout, MAP Kinase Signaling System, Chromosome Disorders, Diffusion Magnetic Resonance Imaging, Mice, DNA Copy Number Variations, Neurodevelopmental Disorders, Gray Matter
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