title: A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells.
abstract: Autism spectrum disorders (ASD) are complex neurodevelopmental diseases in which different combinations of genetic mutations may contribute to the phenotype. Using Rett syndrome (RTT) as an ASD genetic model, we developed a culture system using induced pluripotent stem cells (iPSCs) from RTT patients' fibroblasts. RTT patients' iPSCs are able to undergo X-inactivation and generate functional neurons. Neurons derived from RTT-iPSCs had fewer synapses, reduced spine density, smaller soma size, altered calcium signaling and electrophysiological defects when compared to controls. Our data uncovered early alterations in developing human RTT neurons. Finally, we used RTT neurons to test the effects of drugs in rescuing synaptic defects. Our data provide evidence of an unexplored developmental window, before disease onset, in RTT syndrome where potential therapies could be successfully employed. Our model recapitulates early stages of a human neurodevelopmental disease and represents a promising cellular tool for drug screening, diagnosis and personalized treatment.
authors.affiliation: The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Maria C N
authors.initials: MC
authors.lastname: Marchetto
authors.forename: Cassiano
authors.initials: C
authors.lastname: Carromeu
authors.forename: Allan
authors.initials: A
authors.lastname: Acab
authors.forename: Diana
authors.initials: D
authors.lastname: Yu
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.forename: Yangling
authors.initials: Y
authors.lastname: Mu
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.forename: Alysson R
authors.initials: AR
authors.lastname: Muotri
mesh_terms: D049109:Cell Proliferation; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D055495:Neurogenesis; D015518:Rett Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D013569:Synapses; D049951:X Chromosome Inactivation