title: Abnormal mineralization of the Ts65Dn Down syndrome mouse appendicular skeleton begins during embryonic development in a Dyrk1a-independent manner.
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.
authors.affiliation: Department of Biology, Indiana University-Purdue University Indianapolis and Indiana University Center for Regenerative Biology and Medicine, 723 W. Michigan Street, SL306, Indianapolis, IN 46202, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Blazek
authors.affiliation: Department of Biology, Indiana University-Purdue University Indianapolis and Indiana University Center for Regenerative Biology and Medicine, 723 W. Michigan Street, SL306, Indianapolis, IN 46202, USA.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Malik
authors.affiliation: Department of Biology, Franklin and Marshall College, PO Box 3003, Lancaster, PA 17604, USA.
authors.forename: Maeve
authors.initials: M
authors.lastname: Tischbein
authors.affiliation: Department of Developmental Biology, Institut de Biologia Molecular de Barcelona IBMB- CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona 08028, Spain.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Arbones
authors.affiliation: Department of Biology, Franklin and Marshall College, PO Box 3003, Lancaster, PA 17604, USA.
authors.forename: Clara S
authors.initials: CS
authors.lastname: Moore
authors.affiliation: Department of Biology, Indiana University-Purdue University Indianapolis and Indiana University Center for Regenerative Biology and Medicine, 723 W. Michigan Street, SL306, Indianapolis, IN 46202, USA. Electronic address: rjroper@iupui.edu.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Roper
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047108:Embryonic Development / Q000235:genetics*; D018628:Gene Dosage; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases
keywords: Bone development; Dosage compensation; Down syndrome; Dyrk1a; Trisomy