Morphology, Behavior, and the Sonic Hedgehog Pathway in Mouse Models of Down Syndrome
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Date
2014-07-10
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Johns Hopkins University
Abstract
Down Syndrome (DS) is caused by a triplication of human chromosome 21 (Hsa21). Ts65Dn, a mouse model of DS, contains a freely segregating extra chromosome consisting of the distal portion of mouse chromosome 16 (Mmu16), a region orthologous to part of Hsa21, and a non-Hsa21 orthologous region of mouse chromosome 17. All individuals with DS display some level of craniofacial dysmorphology, brain structural and functional changes, and cognitive impairment. Ts65Dn recapitulates these features of DS and aspects of each of these traits have been linked in Ts65Dn to a reduced response to Sonic Hedgehog (SHH) in trisomic cells.
Dp(16)1Yey is a new mouse model of DS which has a direct duplication of the entire Hsa21 orthologous region of Mmu16. Dp(16)1Yey’s creators found similar behavioral deficits to those seen in Ts65Dn. We performed a quantitative investigation of the skull and brain of Dp(16)1Yey as compared to Ts65Dn and found that DS-like changes to brain and craniofacial morphology were similar in both models. Our results validate examination of the genetic basis for these phenotypes in Dp(16)1Yey mice and the genetic links for these phenotypes previously found in Ts65Dn , i.e., reduced response to SHH.
Further, we hypothesized that if all trisomic cells show a reduced response to SHH, then up-regulation of the SHH pathway might ameliorate multiple phenotypes. We crossed Ts65Dn mice with Ptch1tm1Mps/+ mice, which up-regulate the canonical SHH pathway through the loss of function of one Ptch1 allele. The resulting four mouse genotypes were examined for craniofacial, behavioral and brain phenotypes. We found that Ptch1 heterozygotes displayed craniofacial and behavioral phenotypes that were mostly distinct from the effects of trisomy rather than complementary. However, as predicted some brain structural deficits were ameliorated in the Ts65Dn Ptch1 heterozygotes.
Our studies comprise the first evaluation of Dp(16)1Yey morphology to confirm it as a DS model and our additional DS model investigations indicate a more complex pathogenicity for SHH related phenotypes in DS than constitutive uniform pathway repression.
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Keywords
Down Syndrome, Sonic Hedgehog