Abstract
Down syndrome (DS) is caused by triplication of human chromosome 21 (Hsa21), resulting in skeletal insufficiency and altered postnatal bone development in individuals with DS. DS mouse models have shown similar deficits to humans with DS, mimicking differences between ages, sexes, and bone compartments. The historic mouse model, Ts65Dn, has provided much of the mechanistic insight behind these DS-related skeletal deficits, but there are concerns over its genetic construct validity. Ts65Dn mice have an additional 60 trisomic genes that are homologous to Hsa6. These genes, acting either directly or through interactions with trisomic, Hsa21-homologous or disomic genes, may produce phenotypes not related to DS; so, Ts66Yah mice were derived to remove these genes. After assessing individual densitometric and morphometric parameters in femurs, skeletal phenotypes were directly compared between male and female Ts65Dn and Ts66Yah mice at postnatal day (P) 36 and 6-weeks and between male mice at 16-weeks using multivariate principal components analyses on these parameters. These comparisons confirmed male Ts66Yah mice have trabecular and cortical deficits similar to male Ts65Dn mice at all ages. In contrast, female Ts66Yah mice lacked trabecular deficits evident in female Ts65Dn mice at P36, but both ages had similar cortical deficits. Copy number normalization of Dyrk1a, a trisomic, Hsa21-orthologous gene, failed to rescue deficits in male or improve trabecular bone in female Ts66Yah mice at P36 as observed in Ts65Dn mice. Thus, mechanisms behind trabecular phenotypes in both sexes of Ts66Yah mice likely differ from those of Ts65Dn mice. Overall, the trisomic, Hsa6-homologous genes in Ts65Dn mice may result in differences in trabecular phenotypes or mechanisms prior to 6 weeks but do not impact later trabecular or cortical phenotypes.
Competing Interest Statement
The authors have declared no competing interest.
Data Availability
Data has been uploaded to Dryad (DOI: 10.5061/dryad.kkwh70sf1). Reviewer URL: http://datadryad.org/stash/share/Wc0UyGfRfLvEzlF_FsYoCz7v4KjG9Gn2-y4F3hgutD8.