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PMID:25640183

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Citation

Lee, CT, Bendriem, RM, Kindberg, AA, Worden, LT, Williams, MP, Drgon, T, Mallon, BS, Harvey, BK, Richie, CT, Hamilton, RS, Chen, J, Errico, SL, Tsai, SY, Uhl, GR and Freed, WJ (2015) Functional consequences of 17q21.31/WNT3-WNT9B amplification in hPSCs with respect to neural differentiation. Cell Rep 10:616-32

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.

Links

PubMed PMC4383664 Online version:10.1016/j.celrep.2014.12.050

Keywords

Cell Differentiation/genetics; Cell Differentiation/physiology; Cell Line; Humans; JNK Mitogen-Activated Protein Kinases/metabolism; Neurons/cytology; Neurons/metabolism; Pluripotent Stem Cells/cytology; Pluripotent Stem Cells/metabolism; Signal Transduction; Wnt Proteins/genetics; Wnt Proteins/metabolism; Wnt3 Protein/genetics; Wnt3 Protein/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:FGF2

involved_in

GO:0072089: stem cell proliferation

ECO:0000303: author statement without traceable support used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT3

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

  • regulates_expression_of:(UniProtKB:Q8TE12)

Seeded From UniProt

complete

HUMAN:WNT3

involved_in

GO:0072089: stem cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT3

involved_in

GO:1905474: canonical Wnt signaling pathway involved in stem cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:LMX1A

involved_in

GO:1904948: midbrain dopaminergic neuron differentiation

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT3

involved_in

GO:0050767: regulation of neurogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT3

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000314: direct assay evidence used in manual assertion

P

regulates_expression_of:(ENSEMBL:ENSG00000162761)

Seeded From UniProt

complete

HUMAN:WNT3

involved_in

GO:0072089: stem cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

happens_during:(GO:0008543)

Seeded From UniProt

complete

HUMAN:WNT3

involved_in

GO:1904954: canonical Wnt signaling pathway involved in midbrain dopaminergic neuron differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT3

involved_in

GO:1905474: canonical Wnt signaling pathway involved in stem cell proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

causally_upstream_of:(GO:1904948)

Seeded From UniProt

complete

HUMAN:WNT9B

involved_in

GO:1904948: midbrain dopaminergic neuron differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT9B

involved_in

GO:1902455: negative regulation of stem cell population maintenance

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WNT9B

involved_in

GO:1905438: non-canonical Wnt signaling pathway involved in midbrain dopaminergic neuron differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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