Functional Consequences of 17q21.31/WNT3-WNT9B Amplification in hPSCs with Respect to Neural Differentiation

Chun-Ting Lee; Raphael M. Bendriem; Abigail A. Kindberg; Lila T. Worden; Melanie P. Williams; Tomas Drgon; Barbara S. Mallon; Brandon K. Harvey; Christopher T. Richie; Rebecca S. Hamilton; Jia Chen; Stacie L. Errico; Shang-Yi A. Tsai; George R. Uhl; William J. Freed

doi:10.1016/j.celrep.2014.12.050

Cell Reports (Feb 2015)

Functional Consequences of 17q21.31/WNT3-WNT9B Amplification in hPSCs with Respect to Neural Differentiation

Chun-Ting Lee,
Raphael M. Bendriem,
Abigail A. Kindberg,
Lila T. Worden,
Melanie P. Williams,
Tomas Drgon,
Barbara S. Mallon,
Brandon K. Harvey,
Christopher T. Richie,
Rebecca S. Hamilton,
Jia Chen,
Stacie L. Errico,
Shang-Yi A. Tsai,
George R. Uhl,
William J. Freed

Affiliations

Chun-Ting Lee: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA
Raphael M. Bendriem: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA
Abigail A. Kindberg: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA
Lila T. Worden: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA
Melanie P. Williams: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA
Tomas Drgon: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA
Barbara S. Mallon: NIH Stem Cell Unit, Intramural Research Program, National Institute of Neurological Disorders and Stroke, Department of Health and Human Services, NIH, Bethesda, MD 20892, USA
Brandon K. Harvey: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA
Christopher T. Richie: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA
Rebecca S. Hamilton: NIH Stem Cell Unit, Intramural Research Program, National Institute of Neurological Disorders and Stroke, Department of Health and Human Services, NIH, Bethesda, MD 20892, USA
Jia Chen: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA
Stacie L. Errico: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA
Shang-Yi A. Tsai: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA
George R. Uhl: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA
William J. Freed: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA

DOI: https://doi.org/10.1016/j.celrep.2014.12.050
Journal volume & issue: Vol. 10, no. 4
pp. 616 – 632

Abstract

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Human pluripotent stem cell (hPSC) lines exhibit repeated patterns of genetic variation, which can alter in vitro properties as well as suitability for clinical use. We examined associations between copy-number variations (CNVs) on chromosome 17 and hPSC mesodiencephalic dopaminergic (mDA) differentiation. Among 24 hPSC lines, two karyotypically normal lines, BG03 and CT3, and BG01V2, with trisomy 17, exhibited amplification of the WNT3/WNT9B region and rapid mDA differentiation. In hPSC lines with amplified WNT3/WNT9B, basic fibroblast growth factor (bFGF) signaling through mitogen-activated protein kinase (MAPK)/ERK amplifies canonical WNT signaling by phosphorylating LRP6, resulting in enhanced undifferentiated proliferation. When bFGF is absent, noncanonical WNT signaling becomes dominant due to upregulation of SIAH2, enhancing JNK signaling and promoting loss of pluripotency. When bFGF is present during mDA differentiation, stabilization of canonical WNT signaling causes upregulation of LMX1A and mDA induction. Therefore, CNVs in 17q21.31, a “hot spot” for genetic variation, have multiple and complex effects on hPSC cellular phenotype.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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