Abnormal mineralization of the Ts65Dn Down syndrome mouse appendicular skeleton begins during embryonic development in a Dyrk1a-independent manner. (May 2015)

• Record Type: Journal Article
• Authors: Blazek, Joshua D.; Malik, Ahmed M.; Tischbein, Maeve; Arbones, Maria L.; Moore, Clara S.; Roper, Randall J.
• Is Part Of: Mechanisms of development. Volume 136(2015)
• Page Start: 133
• Page End: 142
• Publication Date: 2015-05
• Subjects: Down syndrome -- Bone development -- Trisomy -- Dosage compensation -- Dyrk1a; Developmental biology -- Periodicals; Molecular biology -- Periodicals; Developmental Biology -- Periodicals; Molecular Biology -- Periodicals; Biologie du développement -- Périodiques; Biologie moléculaire -- Périodiques; Developmental biology; Molecular biology; Periodicals; Electronic journals; 571.8
• DOI: 10.1016/j.mod.2014.12.004
• Languages: English
• ISSNs: 0925-4773

Abstract

Highlights: The altered skeletal phenotype of Ts65Dn mice begins in embryonic development. Ts65Dn embryos show reduced percent bone volume in the developing femur. Altered expression of Dyrk1a does not directly contribute to the embryonic bone phenotype. Nfatc cellular localization is unaffected by trisomy in embryonic femoral anlagen. Abstract: The relationship between gene dosage imbalance and phenotypes associated with Trisomy 21, including the etiology of abnormal bone phenotypes linked to Down syndrome (DS), is not well understood. The Ts65Dn mouse model for DS exhibits appendicular skeletal defects during adolescence and adulthood but the developmental and genetic origin of these phenotypes remains unclear. It is hypothesized that the postnatal Ts65Dn skeletal phenotype originates during embryonic development and results from an increased Dyrk1a gene copy number, a gene hypothesized to play a critical role in many DS phenotypes. Ts65Dn embryos exhibit a lower percent bone volume in the E17.5 femur when compared to euploid embryos. Concomitant with gene copy number, qPCR analysis revealed a ~1.5 fold increase in Dyrk1a transcript levels in the Ts65Dn E17.5 embryonic femur as compared to euploid . Returning Dyrk1a copy number to euploid levels in Ts65Dn, Dyrk1a +/− embryos did not correct the trisomic skeletal phenotype but did return Dyrk1a gene transcript levels to normal. The size and protein expression patterns of the cartilage template during embryonic bone development appear to be unaffected at E14.5 and E17.5 in trisomic embryos. Taken together, these data suggest that the dosage imbalance of genes other than Dyrk1a is involved in the development of the prenatal bone phenotype in Ts65Dn embryos.