Normalization of Dyrk1a in Down syndrome mouse models improves skeletal deficits in a temporal and sex-dependent manner

Down syndrome (DS) is a genetic disorder caused by an additional copy of chromosome 21 (Hsa21). Skeletal deficits are normal in the aging process for individuals without DS; however, individuals with DS develop skeletal deficits earlier in life. This phenomenon is due to the lack of proper bone development and has been linked to three copies of DYRK1A, a gene found on Hsa21. Ts65Dn mice, most commonly used DS mouse model, have three copies of Dyrk1a and exhibit similar skeletal abnormalities as seen in humans with DS. The timeline for which the development of skeletal deficits associated with trisomic Dyrk1a has yet to be determined. Trisomic male Ts65Dn,Dyrk1a+/- mice, which have only two of the three Dyrk1a genes, at postnatal day 42 (P42), or six weeks old, display reduced skeletal deficits. A similar comparison at P30 between Ts65Dn,Dyrk1a+/- and Ts65Dn male and female mice, however, did not ameliorate skeletal deficits. We hypothesized that the normalization of Dyrk1a expression would lead to a lack of skeletal deficits in Ts65Dn,Dyrk1a+/- mice at P36 and are testing this hypothesis via microCT, architectural analysis, and mechanical testing. Our preliminary data at P36 indicate no rescue from skeletal deficits in male and female Ts65Dn,Dyrk1a+/- mice at P36. The data being collected will be influential in the determination of when Dyrk1a influences trisomic skeletal abnormalities; thus, this information will allow for the development of potential therapies to effectively prevent the skeletal abnormalities found in this population in a temporal and sex-dependent manner.