title: Functional consequences of 17q21.31/WNT3-WNT9B amplification in hPSCs with respect to neural differentiation.
abstract: 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.
authors: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA. Electronic address: clee@mail.nih.gov.
authors: Chun-Ting
authors: CT
authors: Lee
authors: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA.
authors: Raphael M
authors: RM
authors: Bendriem
authors: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA.
authors: Abigail A
authors: AA
authors: Kindberg
authors: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA.
authors: Lila T
authors: LT
authors: Worden
authors: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA.
authors: Melanie P
authors: MP
authors: Williams
authors: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA.
authors: Tomas
authors: T
authors: Drgon
authors: 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.
authors: Barbara S
authors: BS
authors: Mallon
authors: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA.
authors: Brandon K
authors: BK
authors: Harvey
authors: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA.
authors: Christopher T
authors: CT
authors: Richie
authors: 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.
authors: Rebecca S
authors: RS
authors: Hamilton
authors: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA.
authors: Jia
authors: J
authors: Chen
authors: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA.
authors: Stacie L
authors: SL
authors: Errico
authors: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA.
authors: Shang-Yi A
authors: SY
authors: Tsai
authors: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA.
authors: George R
authors: GR
authors: Uhl
authors: Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, NIH, Baltimore, MD 21224, USA.
authors: William J
authors: WJ
authors: Freed
mesh_terms: D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C449090:WNT9B protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D048031:JNK Mitogen-Activated Protein Kinases
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