TY - JOUR
T1 - MicroRNA-mediated conversion of human fibroblasts to neurons
AU - Yoo, Andrew S.
AU - Sun, Alfred X.
AU - Li, Li
AU - Shcheglovitov, Aleksandr
AU - Portmann, Thomas
AU - Li, Yulong
AU - Lee-Messer, Chris
AU - Dolmetsch, Ricardo E.
AU - Tsien, Richard W.
AU - Crabtree, Gerald R.
N1 - Funding Information:
Acknowledgements We thank I. Graef and A. Cho for helpful suggestions and reagents, A. Kuo and W. Ho for technical help, and X. Bao and P. Khavari for their generous gift of reagents. A.S.Y. is a fellow of the Helen Hay Whitney Foundation. A.X.S. is funded by the Agency of Science, Technology and Research of Singapore (A*STAR). L.L. is supported by the Stanford Medical Scientist Training Program, National Institutes of Mental Health (NIMH) F30MH093125, and the Frances B. Nelson predoctoral fellowship. A.S. issupportedbythe CIRMpost-doctoralfellowship.T.P.issupportedbyaSwiss National Science Foundation SNSF fellowship for advanced researchers (PA00P3_134196). R.E.D. is supported by the NIH Director’s Award, and awards from the Simon’s Foundation and the CIRM. R.E.D. is also grateful for funding from B. and F. Horowitz, M. McCafferey, B. and J. Packard, P. Kwan and K. Wang. R.W.T. is supported by grants from the Simons, Mathers and Burnett Family Foundations. This work was supported by grants from the Howard Hughes Medical Institute (G.R.C.) and the NIH (HD55391, AI060037 and NS046789 to G.R.C., and NS24067, GM58234 and MH064070 to R.W.T.).
PY - 2011/8/11
Y1 - 2011/8/11
N2 - Neurogenic transcription factors and evolutionarily conserved signalling pathways have been found to be instrumental in the formation of neurons. However, the instructive role of microRNAs (miRNAs) in neurogenesis remains unexplored. We recently discovered that miR-9* and miR-124 instruct compositional changes of SWI/SNF-like BAF chromatin-remodelling complexes, a process important for neuronal differentiation and function. Nearing mitotic exit of neural progenitors, miR-9* and miR-124 repress the BAF53a subunit of the neural-progenitor (np)BAF chromatin-remodelling complex. After mitotic exit, BAF53a is replaced by BAF53b, and BAF45a by BAF45b and BAF45c, which are then incorporated into neuron-specific (n)BAF complexes essential for post-mitotic functions. Because miR-9/9* and miR-124 also control multiple genes regulating neuronal differentiation and function, we proposed that these miRNAs might contribute to neuronal fates. Here we show that expression of miR-9/9* and miR-124 (miR-9/9*-124) in human fibroblasts induces their conversion into neurons, a process facilitated by NEUROD2. Further addition of neurogenic transcription factors ASCL1 and MYT1L enhances the rate of conversion and the maturation of the converted neurons, whereas expression of these transcription factors alone without miR-9/9*-124 was ineffective. These studies indicate that the genetic circuitry involving miR-9/9*-124 can have an instructive role in neural fate determination.
AB - Neurogenic transcription factors and evolutionarily conserved signalling pathways have been found to be instrumental in the formation of neurons. However, the instructive role of microRNAs (miRNAs) in neurogenesis remains unexplored. We recently discovered that miR-9* and miR-124 instruct compositional changes of SWI/SNF-like BAF chromatin-remodelling complexes, a process important for neuronal differentiation and function. Nearing mitotic exit of neural progenitors, miR-9* and miR-124 repress the BAF53a subunit of the neural-progenitor (np)BAF chromatin-remodelling complex. After mitotic exit, BAF53a is replaced by BAF53b, and BAF45a by BAF45b and BAF45c, which are then incorporated into neuron-specific (n)BAF complexes essential for post-mitotic functions. Because miR-9/9* and miR-124 also control multiple genes regulating neuronal differentiation and function, we proposed that these miRNAs might contribute to neuronal fates. Here we show that expression of miR-9/9* and miR-124 (miR-9/9*-124) in human fibroblasts induces their conversion into neurons, a process facilitated by NEUROD2. Further addition of neurogenic transcription factors ASCL1 and MYT1L enhances the rate of conversion and the maturation of the converted neurons, whereas expression of these transcription factors alone without miR-9/9*-124 was ineffective. These studies indicate that the genetic circuitry involving miR-9/9*-124 can have an instructive role in neural fate determination.
UR - http://www.scopus.com/inward/record.url?scp=80051684096&partnerID=8YFLogxK
U2 - 10.1038/nature10323
DO - 10.1038/nature10323
M3 - Letter
C2 - 21753754
AN - SCOPUS:80051684096
VL - 476
SP - 228
EP - 231
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7359
ER -