Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment

Research output: Contribution to journalArticle

E. Yeh, D. Q. Dao, Z. Y. Wu, S. M. Kandalam, F. M. Camacho, C. Tom, W. Zhang, R. Krencik, K. A. Rauen, E. M. Ullian, L. A. Weiss

Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events.

Original languageEnglish (US)
Pages (from-to)1687-1698
Number of pages12
JournalMolecular Psychiatry
Volume23
Issue number8
Early online dateNov 21 2017
DOIs
StatePublished - Aug 1 2018

PMID: 29158583

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Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment. / Yeh, E.; Dao, D. Q.; Wu, Z. Y.; Kandalam, S. M.; Camacho, F. M.; Tom, C.; Zhang, W.; Krencik, R.; Rauen, K. A.; Ullian, E. M.; Weiss, L. A.

In: Molecular Psychiatry, Vol. 23, No. 8, 01.08.2018, p. 1687-1698.

Research output: Contribution to journalArticle

Harvard

Yeh, E, Dao, DQ, Wu, ZY, Kandalam, SM, Camacho, FM, Tom, C, Zhang, W, Krencik, R, Rauen, KA, Ullian, EM & Weiss, LA 2018, 'Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment' Molecular Psychiatry, vol. 23, no. 8, pp. 1687-1698. https://doi.org/10.1038/mp.2017.238

APA

Yeh, E., Dao, D. Q., Wu, Z. Y., Kandalam, S. M., Camacho, F. M., Tom, C., ... Weiss, L. A. (2018). Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment. Molecular Psychiatry, 23(8), 1687-1698. https://doi.org/10.1038/mp.2017.238

Vancouver

Yeh E, Dao DQ, Wu ZY, Kandalam SM, Camacho FM, Tom C et al. Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment. Molecular Psychiatry. 2018 Aug 1;23(8):1687-1698. https://doi.org/10.1038/mp.2017.238

Author

Yeh, E. ; Dao, D. Q. ; Wu, Z. Y. ; Kandalam, S. M. ; Camacho, F. M. ; Tom, C. ; Zhang, W. ; Krencik, R. ; Rauen, K. A. ; Ullian, E. M. ; Weiss, L. A. / Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment. In: Molecular Psychiatry. 2018 ; Vol. 23, No. 8. pp. 1687-1698.

BibTeX

@article{5044a66adf5d4ba1a55b6228533e65ca,
title = "Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment",
abstract = "Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events.",
keywords = "Journal Article",
author = "E. Yeh and Dao, {D. Q.} and Wu, {Z. Y.} and Kandalam, {S. M.} and Camacho, {F. M.} and C. Tom and W. Zhang and R. Krencik and Rauen, {K. A.} and Ullian, {E. M.} and Weiss, {L. A.}",
year = "2018",
month = "8",
day = "1",
doi = "10.1038/mp.2017.238",
language = "English (US)",
volume = "23",
pages = "1687--1698",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "8",

}

RIS

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T1 - Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment

AU - Yeh, E.

AU - Dao, D. Q.

AU - Wu, Z. Y.

AU - Kandalam, S. M.

AU - Camacho, F. M.

AU - Tom, C.

AU - Zhang, W.

AU - Krencik, R.

AU - Rauen, K. A.

AU - Ullian, E. M.

AU - Weiss, L. A.

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events.

AB - Ras/MAPK pathway signaling is a major participant in neurodevelopment, and evidence suggests that BRAF, a key Ras signal mediator, influences human behavior. We studied the role of the mutation BRAFQ257R, the most common cause of cardiofaciocutaneous syndrome (CFC), in an induced pluripotent stem cell (iPSC)-derived model of human neurodevelopment. In iPSC-derived neuronal cultures from CFC subjects, we observed decreased p-AKT and p-ERK1/2 compared to controls, as well as a depleted neural progenitor pool and rapid neuronal maturation. Pharmacological PI3K/AKT pathway manipulation recapitulated cellular phenotypes in control cells and attenuated them in CFC cells. CFC cultures displayed altered cellular subtype ratios and increased intrinsic excitability. Moreover, in CFC cells, Ras/MAPK pathway activation and morphological abnormalities exhibited cell subtype-specific differences. Our results highlight the importance of exploring specific cellular subtypes and of using iPSC models to reveal relevant human-specific neurodevelopmental events.

KW - Journal Article

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U2 - 10.1038/mp.2017.238

DO - 10.1038/mp.2017.238

M3 - Article

VL - 23

SP - 1687

EP - 1698

JO - Molecular Psychiatry

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SN - 1359-4184

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ER -

ID: 37462817