A model for neural development and treatment of rett syndrome using human induced pluripotent stem cells

Maria C.N. Marchetto, Cassiano Carromeu, Allan Acab, Diana Yu, Gene W. Yeo, Yangling Mu, Gong Chen, Fred H. Gage, Alysson R. Muotri

Research output: Contribution to journalArticlepeer-review

958 Citations (SciVal)

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.

Original languageEnglish (US)
Pages (from-to)527-539
Number of pages13
JournalCell
Volume143
Issue number4
DOIs
StatePublished - Nov 12 2010

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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