1. Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment
- Author
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Yeh, E, Dao, DQ, Wu, ZY, Kandalam, SM, Camacho, FM, Tom, C, Zhang, W, Krencik, R, Rauen, KA, Ullian, EM, and Weiss, LA
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Stem Cell Research ,Pediatric ,Regenerative Medicine ,Neurosciences ,Stem Cell Research - Nonembryonic - Human ,Stem Cell Research - Induced Pluripotent Stem Cell ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,1.1 Normal biological development and functioning ,Aetiology ,2.1 Biological and endogenous factors ,Underpinning research ,Neurological ,Cell Culture Techniques ,Ectodermal Dysplasia ,Facies ,Failure to Thrive ,Heart Defects ,Congenital ,Humans ,Induced Pluripotent Stem Cells ,MAP Kinase Signaling System ,Mutation ,Neurogenesis ,Neurons ,Phenotype ,Phosphatidylinositol 3-Kinases ,Phosphoinositide-3 Kinase Inhibitors ,Proto-Oncogene Proteins B-raf ,Proto-Oncogene Proteins c-akt ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Clinical sciences ,Biological psychology ,Clinical and health psychology - 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.
- Published
- 2018