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

• Published in: Molecular psychiatry Vol. 23; no. 8; pp. 1687 - 1698
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2018; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Analysis; Behavioral Sciences; Biological Psychology; Brain research; Cardiofaciocutaneous syndrome; Causes of; Cell Culture Techniques; Ectodermal Dysplasia - metabolism; Ectodermal Dysplasia - pathology; Excitability; Facies; Failure to Thrive - metabolism; Failure to Thrive - pathology; Fibroblasts; Genetic aspects; Heart Defects, Congenital - metabolism; Heart Defects, Congenital - pathology; Human behavior; Humans; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; Inhibitory postsynaptic potentials; MAP kinase; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Medicine; Medicine & Public Health; Mental disorders; Morphology; Mutation; Neurodevelopment; Neurogenesis - drug effects; Neurogenesis - genetics; Neurogenesis - physiology; Neurons; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neurosciences; Pediatrics; Pharmacotherapy; Phenotype; Phenotypes; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors; Pluripotency; Proteins; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Psychiatry; Schizophrenia; Stem cells
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/mp.2017.238

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.