Mechanisms leading to the osteopenic appendicular skeletal phenotype observed in Ts65Dn Down Syndrome mice

Joshua David Blazek, Purdue University

Abstract

Individuals with Down syndrome (DS) exhibit severe appendicular skeletal abnormalities leading to an increased risk of osteoporosis. As the life span of individuals with DS continues to increase, understanding the mechanisms causing the DS bone phenotype is critical to develop therapies to improve quality of life and reduce the impact of age related bone disorders in this population. The Ts65Dn mouse contains nearly half of the genes found in three copies in humans with DS and has been extensively used as a phenotypic model for human DS related abnormalities. I hypothesized that Ts65Dn mice would exhibit an osteopenic appendicular skeleton similar to that observed in humans with DS. Characterization of the Ts65Dn postnatal skeletal phenotype revealed similarities to the human DS appendicular skeletal phenotype leading to further study into the origin of and the genetic and cellular mechanisms causing these abnormalities. Based on our work in postnatal Ts65Dn mice and research in DS showing that many phenotypes originate during embryonic development it was hypothesized that the origin of the abnormal Ts65Dn appendicular skeletal phenotype begins during embryonic development. Analysis of embryonic Ts65Dn mice suggests that the abnormal appendicular bone phenotype originates in the later stages of embryonic bone development with a lower percent bone volume present in the embryonic bone precursor. Genetically, Dual specificity tyrosine kinase 1a (DYRK1A) is a gene found in three copies in both humans with DS and the Ts65Dn mouse model and is hypothesized to be involved in the origin of several DS phenotypes. Evidence in a Dyrk1a overexpressing transgenic mouse model showed that these mice exhibit a bone phenotype similar to what was observed in the Ts65Dn mouse model. I hypothesized that Dyrk1a gene copy number is a critical contributor to the abnormal Ts65Dn appendicular skeletal phenotype and used both a genetic and a therapeutic approach to test this hypothesis. Genetically, return of Dyrk1a copy number to euploid levels in Ts65Dn, Dyrk1a +/- mice led to a significant improvement in the abnormal postnatal appendicular skeleton and rescued the majority of the phenotype to euploid levels. Surprisingly, the embryonic bone phenotype was not influenced by Dyrk1a gene copy number in Ts65Dn embryos. Therapeutically, treatment of Ts65Dn mice with the EGCG improved the appendicular bone phenotype, however these effects were not as complete as those observed in Ts65Dn, Dyrk1a+/- mice. Future research needs to be done to better understand how Dyrk1a overexpression alters the downstream pathways affecting bone cell development and activity. Additionally, a longer EGCG treatment period is needed to fully determine the efficacy of therapeutic treatment against Dyrk1a overexpression in Ts65Dn mice.

Degree

Ph.D.

Advisors

Konieczny, Purdue University.

Subject Area

Genetics|Developmental biology

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