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

Starbuck, John M.; Dutka, Tara; Ratliff, Tabetha S.; Reeves, Roger H.; Richtsmeier, Joan T.

doi:10.1002/ajmg.a.36594

Cited by 43 publications

(48 citation statements)

References 37 publications

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“…Mice were sacrificed as soon as MB symptoms developed or up to 2 weeks following the final test (age 4–5.5 months) as in Starbuck et al (2014). The brains of a subset of mice from both behavioral data sets were processed and data collected for assessment of cerebellar area and GC density as described (Starbuck et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

“…The brains of a subset of mice from both behavioral data sets were processed and data collected for assessment of cerebellar area and GC density as described (Starbuck et al, 2014). Brains from Ptch1 +/− mice, both euploid and Ts65Dn, were screened for the presence of large MBs.…”

Section: Methodsmentioning

confidence: 99%

“…Mice with tumors disrupting the cerebellar architecture were eliminated from the histological assessment of cerebellar structure. Three brains containing MBs were prepared and sectioned as in Starbuck et al (2014). The whole and half Ptch1 +/− brains remaining were sectioned, stained with Lac-z, and examined for MBs.…”

Section: Methodsmentioning

confidence: 99%

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Chronic up-regulation of the SHH pathway normalizes some developmental effects of trisomy in Ts65Dn mice

Dutka

Hallberg

Reeves

2015

Mechanisms of Development

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Down Syndrome (DS) is a highly complex developmental genetic disorder caused by trisomy for human chromosome 21 (Hsa21). All individuals with DS exhibit some degree of brain structural changes and cognitive impairment; mouse models such as Ts65Dn have been instrumental in understanding the underlying mechanisms. Several phenotypes of DS might arise from a reduced response of trisomic cells to the Sonic Hedgehog (SHH) growth factor. If all trisomic cells show a similar reduced response to SHH, then up-regulation of the pathway in trisomic cells might ameliorate multiple DS phenotypes. We crossed Ptch1tm1Mps/+ mice, in which the canonical SHH pathway is expected to be up-regulated in every SHH-responsive cell due to the loss of function of one allele of the pathway suppressor, Ptch1, to the Ts65Dn DS model and assessed the progeny for possible rescue of multiple DS-related phenotypes. Down-regulation of Ptch produced several previously unreported effects on development by itself, complicating interpretation of some phenotypes, and a number structural or behavioral effects of trisomy were not compensated by SHH signaling. However, a deficit in a nest-building task was partially restored in Ts;Ptch+/− mice, as were structural anomalies of the cerebellum in Ts65Dn mice. These results extend the body of evidence indicating that reduced response to SHH in trisomic cells and tissues contributes to various aspects of the trisomic phenotype.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Chronic up-regulation of the SHH pathway normalizes some developmental effects of trisomy in Ts65Dn mice

Dutka

Hallberg

Reeves

2015

Mechanisms of Development

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“…Twenty-three orthologs of Hsa21 genes plus a cluster of KRTAP-related genes that are trisomic in Ts65Dn are not triplicated in Ts1Cje (Starbuck et al 2014). We identified 14 of these that are expressed in the developing heart ( Figure 1B) (http://www.tigem.it/ch21exp/AtlasNewL.html; http://www.genecards.org/; http://www.ncbi.nlm.nih.gov/ pubmed).…”

Section: Trisomy For Jam2 Acts In Concert With Creld1mentioning

confidence: 99%

Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier

Edie

Klinedinst

et al. 2016

Genetics

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Down syndrome (DS) is a significant risk factor for congenital heart disease (CHD), increasing the incidence 50 times over the general population. However, half of people with DS have a normal heart and thus trisomy 21 is not sufficient to cause CHD by itself. Ts65Dn mice are trisomic for orthologs of .100 Hsa21 genes, and their heart defect frequency is significantly higher than their euploid littermates. Introduction of a null allele of Creld1 into Ts65Dn increases the penetrance of heart defects significantly. However, this increase was not seen when the Creld1 null allele was introduced into Ts1Cje, a mouse that is trisomic for about two thirds of the Hsa21 orthologs that are triplicated in Ts65Dn. Among the 23 genes present in three copies in Ts65Dn but not Ts1Cje, we identified Jam2 as necessary for the increased penetrance of Creld1-mediated septal defects in Ts65Dn. Thus, overexpression of the trisomic gene, Jam2, is a necessary potentiator of the disomic genetic modifier, Creld1. No direct physical interaction between Jam2 and Creld1 was identified by several methods. Regions of Hsa21 containing genes that are risk factors of CHD have been identified, but Jam2 (and its environs) has not been linked to heart formation previously. The complexity of this interaction may be more representative of the clinical situation in people than consideration of simple single-gene models.

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“…Among its known substrates are transcription factors, splicing factors, endocytic scaffolding proteins, and Hsa21-encoded proteins. Transgenic mice overexpressing Dyrk1a from human or mouse genomic constructs display, among other features, deficits in the Morris water maze (MWM) (Ahn et al 2006; Souchet et al 2014). However, the Ts1Rhr that is trisomic for Dyrk1a plus ~30 additional genes shows normal MWM performance (Olsen et al 2007).…”

Section: Gene-phenotype Correlationsmentioning

confidence: 99%

Mouse models of Down syndrome: gene content and consequences

2016

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Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), is challenging to model in mice. Not only is it a contiguous gene syndrome spanning 35 Mb of the long arm of Hsa21, but orthologs of Hsa21 genes map to segments of three mouse chromosomes, Mmu16, Mmu17 and Mmu10. The Ts65Dn was the first viable segmental trisomy mouse model for DS; it is a partial trisomy currently popular in preclinical evaluations of drugs for cognition in DS. Limitations of the Ts65Dn are: (i) it is trisomic for 125 human protein coding orthologs, but only 90 of these are Hsa21 orthologs; and (ii) it lacks trisomy for ~75 Hsa21 orthologs. In recent years, several additional mouse models of DS have been generated, each trisomic for a different subset of Hsa21 genes or their orthologs. To best exploit these models and interpret results obtained with them, prior to proposing clinical trials, an understanding of their trisomic gene content, relative to full trisomy 21, is necessary. Here we first review functional information on Hsa21 protein coding genes and the more recent annotation of a large number of functional RNA genes. We then discuss the conservation and genomic distribution of Hsa21 orthologs in the mouse genome and the distribution of mouse-specific genes. Lastly, we consider the strengths and weaknesses of mouse models of DS based on the number and nature of the Hsa21 orthologs that are, and are not, trisomic in each, and discuss their validity for use in preclinical evaluations of drug responses.

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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

Cited by 43 publications

References 37 publications

Chronic up-regulation of the SHH pathway normalizes some developmental effects of trisomy in Ts65Dn mice

Chronic up-regulation of the SHH pathway normalizes some developmental effects of trisomy in Ts65Dn mice

Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier

Mouse models of Down syndrome: gene content and consequences

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