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

Molecular Psychiatryvolume 23pages16871698 (2018) | Download Citation



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 BRAF Q257R, 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.

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This work was supported by National Institutes of Health New Innovator (1DP2OD007449 to LAW), Simons Foundation Autism Research Initiative (to LAW and EMU), National Alliance for Research on Schizophrenia and Depression Young Investigator Grant from the Brain & Behavior Research Foundation (to EY), Staglin Family/ International Mental Health Research Organization Assistant Professorship (to LAW), University of California San Francisco Resource Allocation Program (to LAW and WZ), the LeJeune Foundation (to LAW and EY), the City College of San Francisco Bridges to Stem Cell Program (to ZYW, FMC and CT), National Institutes of Health (T32 EY007120 to DQD), Research to Prevent Blindness—Walt and Lilly Disney Award for Amblyopia Research (to DQD) and National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (5RO1AR062165 to KAR). We thank all of the participants in our study and their families; Dina Bseiso and Dr Alinoë Lavillaureix for collecting and reviewing the patients’ clinical data; Brigid Adviento and Dr Keren Messing-Guy for preparing and shipping the skin biopsies; Dr Michela Traglia for help with repeated measures ANOVA; Dr Arnold Kriegstein’s lab (UCSF), and, specifically, Dr Alex Pollen for kindly providing the control iPSC line HS1-11; Dr Jody Baron (UCSF) for allowing us to use the QuantStudio 6 Flex Real-Time PCR System; Dr Susan M. Voglmaier’s lab (UCSF) and, specifically Dr Magda Santos for generously providing anti-GAD65 and anti-GAD67 antibodies; Liorimar R Medina and John Paul Kwak for technical assistance; and Jody Williams, MA, for revision of the manuscript and department assistance. We also thank NF, Children's Tumor Foundation, Noonan Foundation, CFC International, Costello Syndrome Family Support Network, Costello Kids and RASopathy Network for their contribution to our recruitment efforts.

Author information


  1. Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA

    • E Yeh
    • , Z Y Wu
    • , S M Kandalam
    • , F M Camacho
    • , C Tom
    • , W Zhang
    •  & L A Weiss
  2. Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, USA

    • D Q Dao
    • , R Krencik
    •  & E M Ullian
  3. Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA

    • R Krencik
  4. Department of Pediatrics, University of California, Davis, Sacramento, CA, USA

    • K A Rauen
  5. Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA

    • K A Rauen
  6. Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA

    • K A Rauen
    •  & L A Weiss


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The authors declare no conflict of interest.

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Correspondence to L A Weiss.

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