TY - JOUR
T1 - A model for neural development and treatment of rett syndrome using human induced pluripotent stem cells
AU - Marchetto, Maria C.N.
AU - Carromeu, Cassiano
AU - Acab, Allan
AU - Yu, Diana
AU - Yeo, Gene W.
AU - Mu, Yangling
AU - Chen, Gong
AU - Gage, Fred H.
AU - Muotri, Alysson R.
N1 - Funding Information:
The work was supported by the Emerald Foundation and by the National Institutes of Health through the NIH Director's New Innovator Award Program, 1-DP2-OD006495-01. F.H.G. is supported by California Institute for Regenerative Medicine RL1-00649-1 and RC1-00115-1, The Lookout Fund and the Mathers Foundation. C.C. is a fellow from the International Rett Syndrome Foundation. M.C.N.M. is a Christopher and Danna Reeve Foundation fellow. G.C. was supported by the Glenn Foundation. We would like to thank Monica Coenraads for critical discussion; the Greenwood Genetic Center clinical diagnostic laboratory for X-inactivation analysis; Dr. Jeannie T. Lee for the Xist probe; and M.L. Gage for editorial comments.
PY - 2010/11/12
Y1 - 2010/11/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=78149488365&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78149488365&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2010.10.016
DO - 10.1016/j.cell.2010.10.016
M3 - Article
C2 - 21074045
AN - SCOPUS:78149488365
SN - 0092-8674
VL - 143
SP - 527
EP - 539
JO - Cell
JF - Cell
IS - 4
ER -