Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 May 29;8(1):109.
doi: 10.1038/s41398-018-0157-z.

Linking spatial gene expression patterns to sex-specific brain structural changes on a mouse model of 16p11.2 hemideletion

Vinod Jangir Kumar  1   2   3 , Nicola M Grissom  4   5   6 , Sarah E McKee  4   5 , Hannah Schoch  5   7 , Nicole Bowman  5   8 , Robbert Havekes  9 , Manoj Kumar  10 , Stephen Pickup  10 , Harish Poptani  10   11 , Teresa M Reyes  4   5   12 , Mike Hawrylycz  13 , Ted Abel  14 , Thomas Nickl-Jockschat  15   16   17   18
Affiliations

Linking spatial gene expression patterns to sex-specific brain structural changes on a mouse model of 16p11.2 hemideletion

Vinod Jangir Kumar et al. Transl Psychiatry. .

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Schematic overview over the alignment process of ISH maps from the Allen Mouse Atlas to Waxholm space.
The Allen Mouse Brain Explorer usually displays the gene expression map of interest superimposed over the Nissl stainings (1). Conventional alignment algorithms do not properly transform these images into a standard anatomical space. Therefore, both data sets—i.e., the Nissl-stained images and the gene expression maps—were treated separately and 3D reconstructed in a first step (2). We used linear registration algorithm to align the NIFTI of Nissl-stained slides to Waxholm standard space (3). We then used the resulting deformation field on the NIFTI files of each gene expression map and, thus, aligned them to Waxholm space (4). We next linearly registered the mean FA skeleton derived from our TBSS analysis to the corresponding skull-stripped T1-weighted brain scan of the same animal (5). The T1-weighted images were then registered to Waxholm space (6). This step enabled us to transfer the clusters obtained by our TBSS analysis from diffusion space to Waxholm space and directly compare them to the gene expression maps
Fig. 2
Fig. 2. Overview over the different steps of creating registration matrices to adjust the images for the different resolution scales.
This is a pivotal step to optimize conditions for a proper alignment process. Low-resolution Allen Nissl space (200 microns isotropic) (a) are up-sampled to high-resolution Nissl space (25 microns) (b). Nissl-stained images are then converted into gray-scaled Nissl space (c). This step was necessary because gray-scaled images provided a better contrast for the following registration to 21.5 isotropic T2-fweighted Waxholm space (d)
Fig. 3
Fig. 3. Fiber tract changes in female (left) and male (right) del/+ animals compared to wild types of the same sex.
Increases of fractional anisotropy (FA) in the del/+ animals are displayed in red, FA decreases in blue. The mean fiber tract skeleton is displayed in green. We found widespread decreased FA in both male and female del/+. In female del/+, FA decreases were detectable in fiber tracts throughout telencephalic and cerebellar regions, with increased FA only in small cerebellar regions. In male del/+ animals, we found pronounced FA increases in medial and peristriatal fiber tracts
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Malhotra D, Sebat J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell. 2012;148:1223–1241. doi: 10.1016/j.cell.2012.02.039. - DOI - PMC - PubMed
    1. Sebat J, et al. Strong association of de novo copy number mutations with autism. Science. 2007;316:445–449. doi: 10.1126/science.1138659. - DOI - PMC - PubMed
    1. Pinto D, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466:368–372. doi: 10.1038/nature09146. - DOI - PMC - PubMed
    1. Sanders SJ, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011;70:863–885. doi: 10.1016/j.neuron.2011.05.002. - DOI - PMC - PubMed
    1. Levy D, et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron. 2011;70:886–897. doi: 10.1016/j.neuron.2011.05.015. - DOI - PubMed

MeSH terms

Supplementary concepts

LinkOut - more resources