Sex specific emergence of trisomicDyrk1a-related skeletal phenotypes in the development of a Down syndrome mouse model

Abstract

AbstractSkeletal insufficiency affects all individuals with Down syndrome (DS) or Trisomy 21 (Ts21) and may alter bone strength throughout development due to a reduced period of bone formation and early attainment of peak bone mass compared to typically developing individuals. Appendicular skeletal deficits also appear in males before females with DS. In femurs of male Ts65Dn DS model mice, cortical deficits were pronounced throughout development, but trabecular deficits andDyrk1aoverexpression were transitory until postnatal day (P) 30 when there were persistent trabecular and cortical deficits andDyrk1awas trending overexpression. Correction of DS-related skeletal deficits by a purported DYRK1A inhibitor or through genetic means beginning at P21 was not effective at P30, but germline normalization ofDyrk1aimproved male bone structure by P36. Trabecular and cortical deficits in female Ts65Dn mice were evident at P30 but subsided by P36, typifying periodic developmental skeletal normalizations that progressed to more prominent bone deficiencies. Sex-dependent differences in skeletal deficits with a delayed impact of trisomicDyrk1aare important to find temporally specific treatment periods for bone and other phenotypes associated with Ts21.Summary StatementAnalyzing developing bone and gene expression in Ts65Dn Down syndrome model mice revealed timepoints during development when trisomicDyrk1aoverexpression linked to appendicular skeletal abnormalities.Dyrk1awas not always overexpressed.