Complex contributions of Ets2 to craniofacial and thymus phenotypes of trisomic “Down syndrome” mice

Authors

  • Cheryl A. Hill,

    1. Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania
    Current affiliation:
    1. University of Missouri School of Medicine, Columbia, MO.
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  • Thomas E. Sussan,

    1. Department of Physiology, McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Current affiliation:
    1. Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
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  • Roger H. Reeves,

    1. Department of Physiology, McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Joan T. Richtsmeier

    Corresponding author
    1. Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania
    2. Center for Functional Anatomy and Evolution, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • Department of Anthropology, Pennsylvania State University, 409 Carpenter Building, University Park, PA 16802.
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  • How to cite this article: Hill CA, Sussan TE, Reeves RH, Richtsmeier JT. 2009. Complex contributions of Ets2 to craniofacial and thymus phenotypes of trisomic “Down syndrome” mice. Am J Med Genet Part A 149A:2158–2165.

Abstract

Ts65Dn mice have segmental trisomy for orthologs of about half of the genes on human chromosome 21, including Ets2. These mice develop anomalies of the cranial skeleton and thymus that parallel those in Down syndrome. Overexpression of the Ets2 transcription factor gene was posited to be sufficient to produce these craniofacial and thymus deficits in transgenic mice that constitutively overexpress a processed Ets2 transcript under a promiscuous promoter [Sumarsono et al. (1996); Nature 379:534–537; Wolvetang et al. (2003); Hum Mol Genet 12:247–255]. Evaluation of trisomic mice with varying copy numbers of a properly regulated Ets2 gene indicated increased dosage of Ets2 was not sufficient to produce effects on thymus and most of the cranial anomalies seen in Ts65Dn mice. However, mesoderm-derived cranial skeletal elements are significantly more affected in Ts65Dn, Ets2+/− mice compared to Ts65Dn littermates suggesting a differential interaction of Ets2-related processes with mesoderm-derived and neural crest-derived formative tissues. Our results support the growing evidence for interactions among multiple genes contributing to developmental perturbations resulting in variation in complex Down syndrome phenotypes. © 2009 Wiley-Liss, Inc.

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