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

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

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16 Scopus citations

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 language	English (US)
Pages (from-to)	616-632
Number of pages	17
Journal	Cell Reports
Volume	10
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2014.12.050
State	Published - Feb 3 2015
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2014.12.050

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Lee, C. T., Bendriem, R. M., Kindberg, A. A., Worden, L. T., Williams, M. P., Drgon, T., Mallon, B. S., Harvey, B. K., Richie, C. T., Hamilton, R. S., Chen, J., Errico, S. L., Tsai, S. Y. A., Uhl, G. R., & Freed, W. J. (2015). Functional consequences of 17q21.31/WNT3-WNT9B amplification in hPSCs with respect to neural differentiation. Cell Reports, 10(4), 616-632. https://doi.org/10.1016/j.celrep.2014.12.050

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, SYA, Uhl, GR & Freed, WJ 2015, 'Functional consequences of 17q21.31/WNT3-WNT9B amplification in hPSCs with respect to neural differentiation', Cell Reports, vol. 10, no. 4, pp. 616-632. https://doi.org/10.1016/j.celrep.2014.12.050

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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 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.",

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AU - Worden, Lila T.

AU - Williams, Melanie P.

AU - Drgon, Tomas

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AU - Harvey, Brandon K.

AU - Richie, Christopher T.

AU - Hamilton, Rebecca S.

AU - Chen, Jia

AU - Errico, Stacie L.

AU - Tsai, Shang Yi A

AU - Uhl, George R.

AU - Freed, William J.

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AB - 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.

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Functional consequences of 17q21.31/WNT3-WNT9B amplification in hPSCs with respect to neural differentiation

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