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Patient-derived iPSCs show premature neural differentiation and neuron type-specific phenotypes relevant to neurodevelopment
- Source :
- Molecular psychiatry, vol 23, iss 8
- Publication Year :
- 2018
- Publisher :
- eScholarship, University of California, 2018.
-
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.
- Subjects :
- Neurons
Proto-Oncogene Proteins B-raf
Psychiatry
MAP Kinase Signaling System
Neurogenesis
Induced Pluripotent Stem Cells
Psychology and Cognitive Sciences
Cell Culture Techniques
Facies
Biological Sciences
Medical and Health Sciences
Failure to Thrive
Congenital
Phosphatidylinositol 3-Kinases
Phenotype
Ectodermal Dysplasia
Mutation
Humans
Proto-Oncogene Proteins c-akt
Heart Defects
Phosphoinositide-3 Kinase Inhibitors
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Molecular psychiatry, vol 23, iss 8
- Accession number :
- edsair.od.......325..3b009b3cc9f807ff57f855c5c6b3f4ab