10779/crick.12472682.v1
Jared R Thomas
Jared R
Thomas
Jonathan LaCombe
Jonathan
LaCombe
Rachel Long
Rachel
Long
Eva Lana-Elola
Eva
Lana-Elola
Sheona Watson-Scales
Sheona
Watson-Scales
Joseph M Wallace
Joseph M
Wallace
Elizabeth MC Fisher
Elizabeth MC
Fisher
Victor LJ Tybulewicz
Victor LJ
Tybulewicz
Randall J Roper
Randall J
Roper
Interaction of sexual dimorphism and gene dosage imbalance in skeletal deficits associated with Down syndrome.
The Francis Crick Institute
2020
Developmental modeling
Genetic animal models
Osteoporosis
Sexual dimorphism
Skeletal abnormalities
Trisomy 21
Tybulewicz FC001194
Endocrinology & Metabolism
11 Medical and Health Sciences
06 Biological Sciences
09 Engineering
2020-06-25 13:56:23
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Interaction_of_sexual_dimorphism_and_gene_dosage_imbalance_in_skeletal_deficits_associated_with_Down_syndrome_/12472682
All individuals with Down syndrome (DS), which results from trisomy of human chromosome 21 (Ts21), present with skeletal abnormalities typified by craniofacial features, short stature and low bone mineral density (BMD). Differences in skeletal deficits between males and females with DS suggest a sexual dimorphism in how trisomy affects bone. Dp1Tyb mice contain three copies of all of the genes on mouse chromosome 16 that are homologous to human chromosome 21, males and females are fertile, and therefore are an excellent model to test the hypothesis that gene dosage influences the sexual dimorphism of bone abnormalities in DS. Dp1Tyb as compared to control littermate mice at time points associated with bone accrual (6 weeks) and skeletal maturity (16 weeks) showed deficits in BMD and trabecular architecture that occur largely through interactions between sex and genotype and resulted in lower percent bone volume in all female and Dp1Tyb male mice. Cortical bone in Dp1Tyb as compared to control mice exhibited different changes over time influenced by sex × genotype interactions including reduced cortical area in both male and female Dp1Tyb mice. Mechanical testing analyses suggested deficits in whole bone properties such as bone mass and geometry, but improved material properties in female and Dp1Tyb mice. Sexual dimorphisms and the influence of trisomic gene dosage differentially altered cellular properties of male and female Dp1Tyb bone. These data establish sex, gene dosage, skeletal site and age as important factors in skeletal development of DS model mice, paving the way for identification of the causal dosage-sensitive genes. Skeletal differences in developing male and female Dp1Tyb DS model mice replicated differences in less-studied adolescents with DS and established a foundation to understand the etiology of trisomic bone deficits.