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

Research output: Contribution to journalArticlepeer-review

Abstract

Human pluripotent stem cell (hPSC) lines exhibit repeated patterns of genetic variation, which can alter invitro 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.

Original languageEnglish (US)
Pages (from-to)616-632
Number of pages17
JournalCell Reports
Volume10
Issue number4
DOIs
StatePublished - Feb 3 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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