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

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

Research output: Contribution to journalArticle

4 Scopus citations

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.

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

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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    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. (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