Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice - PubMed (original) (raw)

Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice

John M Starbuck et al. Am J Med Genet A. 2014 Aug.

Abstract

Trisomy 21 results in gene-dosage imbalance during embryogenesis and throughout life, ultimately causing multiple anomalies that contribute to the clinical manifestations of Down syndrome. Down syndrome is associated with manifestations of variable severity (e.g., heart anomalies, reduced growth, dental anomalies, shortened life-span). Craniofacial dysmorphology and cognitive dysfunction are consistently observed in all people with Down syndrome. Mouse models are useful for studying the effects of gene-dosage imbalance on development. We investigated quantitative changes in the skull and brain of the Dp(16)1Yey Down syndrome mouse model and compared these mice to Ts65Dn and Ts1Cje mouse models. Three-dimensional micro-computed tomography images of Dp(16)1Yey and euploid mouse crania were morphometrically evaluated. Cerebellar cross-sectional area, Purkinje cell linear density, and granule cell density were evaluated relative to euploid littermates. Skulls of Dp(16)1Yey and Ts65Dn mice displayed similar changes in craniofacial morphology relative to their respective euploid littermates. Trisomy-based differences in brain morphology were also similar in Dp(16)1Yey and Ts65Dn mice. These results validate examination of the genetic basis for craniofacial and brain phenotypes in Dp(16)1Yey mice and suggest that they, like Ts65Dn mice, are valuable tools for modeling the effects of trisomy 21 on development.

Keywords: Down syndrome; brain morphology; craniofacial morphogenesis; gene-dosage imbalance; trisomy 21.

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Figures

FIG. 1

Linear distances that are significantly different by confidence interval testing (α = 0.10) and differ by ≥3% between Dp(16)1Yey mice and euploid littermates. Lateral (A), superior (B), and inferior (C) views of the mouse cranium and superior (D) and lateral (E) views of the mandible are provided. Linear distances that are significantly smaller (solid) and larger (dashed) in Dp(16)1Yey trisomic mice relative to euploid are depicted. Color figure can be viewed in the online issue, which is available at

http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833

FIG. 2

Principal coordinates analysis results for Dp(16)1Yey trisomic (TS) and euploid mice (EU). TS mice are depicted as squares with a dotted convex hull outline, and EU mice are depicted as circles with a solid convex hull outline. (A) Distribution of individuals along principal coordinate axes 1 and 2 (PC1 and PC2) estimated in the analysis of the skull. Linear distances that are strongly correlated with the negative and positive ends of the PC axes are depicted on the skulls. (B) Distribution of individuals along PC1 and PC2 for the mandibular analysis. Linear distances that are most strongly correlated with the positive and negative ends of the PC axes are shown on the mandibles. Color figure can be viewed in the online issue, which is available at

http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833

FIG. 3

Linear distances with significantly different variances between Dp(16)1Yey mice and euploid littermates. Lateral (A), superior (B), and inferior (C) views of the mouse cranium and superior (D) and lateral (E) views of the mandible are provided. Significant differences showing increased (solid) and decreased variances (dashed) in Dp(16)1Yey trisomic mice relative to euploid are depicted. Color figure can be viewed in the online issue, which is available at

http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833

FIG. 4

Relative differences between crania of Dp(16)1Yey mice and euploid littermates are more similar to differences between Ts65Dn and euploid littermates than those defined between Ts1Cje mice and euploid littermates. Dashed lines represent linear distances that exhibit differences of significantly larger magnitude between Dp(16)1Yey mice and euploid littermates relative to Ts65Dn mice and euploid littermates (A and B) or relative to Ts1Cje mice and euploid littermates (C and D). Solid lines represent linear distances that exhibit differences that are significantly larger in the comparison of Ts1Cje mice and euploid littermates relative to Dp(16)1Yey mice and euploid littermates (C and D). Color figure can be viewed in the online issue, which is available at

http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833

FIG. 5

Dp(16)1Yey mice are significantly reduced in cerebellar midline area measurements, Purkinje cell density, and cerebellar granule cell density. Graphical representation of (A) the average midline cerebellar area as a fraction of the total brain area for each mouse as well as the overall average ratio for each ploidy; (B) the average Purkinje cell density in cells per mm for each mouse as well as the overall average for each ploidy; (C) the average cerebellar granule cell density in cells per mm2 for each mouse as well as the overall average for each ploidy.

FIG. 6

Dp(16)1Yey mice are not significantly different from Ts65Dn in cerebellar midline area measurements, Purkinje cell density, or cerebellar granule cell density relative to euploid, but are significantly different from Ts1Cje in linear Purkinje cell density relative to euploid. Graphical representation of the indices of (A) midline cerebellar area as a fraction of the total brain area as compared to euploid; (B) linear Purkinje cell density as compared to euploid; (C) cerebellar granule cell density as compared to euploid in each model.

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Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice - PubMed (original) (raw)