The Ink4a/Arf locus is a barrier to direct neuronal transdifferentiation. Price, J. D, Park, K., Chen, J., Salinas, R. D, Cho, M. J, Kriegstein, A. R, & Lim, D. A J Neurosci, 34(37):12560–12567, September, 2014. abstract bibtex Non-neurogenic cell types, such as cortical astroglia and fibroblasts, can be directly converted into neurons by the overexpression of defined transcription factors. Normally, the cellular phenotype of such differentiated cells is remarkably stable and resists direct cell transdifferentiation. Here we show that the Ink4a/Arf (also known as Cdkn2a) locus is a developmental barrier to direct neuronal transdifferentiation induced by transcription factor overexpression. With serial passage in vitro, wild-type postnatal cortical astroglia become progressively resistant to Dlx2-induced neuronal transdifferentiation. In contrast, the neurogenic competence of Ink4a/Arf-deficient astroglia is both greatly increased and does not diminish through serial cell culture passage. Electrophysiological analysis further demonstrates the neuronal identity of cells induced from Ink4a/Arf-null astroglia, and short hairpin RNA-mediated acute knockdown of p16Ink4a and p19Arf p16(Ink4a) and p19(Arf) indicates that these gene products function postnatally as a barrier to cellular transdifferentiation. Finally, we found that mouse fibroblasts deficient for Ink4a/Arf also exhibit greatly enhanced transcription factor-induced neuronal induction. These data indicate that Ink4a/Arf is a potent barrier to direct neuronal transdifferentiation and further suggest that this locus functions normally in the progressive developmental restriction of postnatal astrocytes.
@ARTICLE{Price2014-lp,
title = "The {Ink4a/Arf} locus is a barrier to direct neuronal
transdifferentiation",
author = "Price, James D and Park, Ki-Youb and Chen, Jiadong and Salinas,
Ryan D and Cho, Mathew J and Kriegstein, Arnold R and Lim, Daniel
A",
abstract = "Non-neurogenic cell types, such as cortical astroglia and
fibroblasts, can be directly converted into neurons by the
overexpression of defined transcription factors. Normally, the
cellular phenotype of such differentiated cells is remarkably
stable and resists direct cell transdifferentiation. Here we show
that the Ink4a/Arf (also known as Cdkn2a) locus is a
developmental barrier to direct neuronal transdifferentiation
induced by transcription factor overexpression. With serial
passage in vitro, wild-type postnatal cortical astroglia become
progressively resistant to Dlx2-induced neuronal
transdifferentiation. In contrast, the neurogenic competence of
Ink4a/Arf-deficient astroglia is both greatly increased and does
not diminish through serial cell culture passage.
Electrophysiological analysis further demonstrates the neuronal
identity of cells induced from Ink4a/Arf-null astroglia, and
short hairpin RNA-mediated acute knockdown of p16Ink4a and p19Arf
p16(Ink4a) and p19(Arf) indicates that these gene products
function postnatally as a barrier to cellular
transdifferentiation. Finally, we found that mouse fibroblasts
deficient for Ink4a/Arf also exhibit greatly enhanced
transcription factor-induced neuronal induction. These data
indicate that Ink4a/Arf is a potent barrier to direct neuronal
transdifferentiation and further suggest that this locus
functions normally in the progressive developmental restriction
of postnatal astrocytes.",
journal = "J Neurosci",
volume = 34,
number = 37,
pages = "12560--12567",
month = sep,
year = 2014,
keywords = "Ink4a/Arf; astroglia; induced neuron; transcription factor;
transdifferentiation",
language = "en"
}
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A"],"bibdata":{"bibtype":"article","type":"article","title":"The Ink4a/Arf locus is a barrier to direct neuronal transdifferentiation","author":[{"propositions":[],"lastnames":["Price"],"firstnames":["James","D"],"suffixes":[]},{"propositions":[],"lastnames":["Park"],"firstnames":["Ki-Youb"],"suffixes":[]},{"propositions":[],"lastnames":["Chen"],"firstnames":["Jiadong"],"suffixes":[]},{"propositions":[],"lastnames":["Salinas"],"firstnames":["Ryan","D"],"suffixes":[]},{"propositions":[],"lastnames":["Cho"],"firstnames":["Mathew","J"],"suffixes":[]},{"propositions":[],"lastnames":["Kriegstein"],"firstnames":["Arnold","R"],"suffixes":[]},{"propositions":[],"lastnames":["Lim"],"firstnames":["Daniel","A"],"suffixes":[]}],"abstract":"Non-neurogenic cell types, such as cortical astroglia and fibroblasts, can be directly converted into neurons by the overexpression of defined transcription factors. Normally, the cellular phenotype of such differentiated cells is remarkably stable and resists direct cell transdifferentiation. Here we show that the Ink4a/Arf (also known as Cdkn2a) locus is a developmental barrier to direct neuronal transdifferentiation induced by transcription factor overexpression. With serial passage in vitro, wild-type postnatal cortical astroglia become progressively resistant to Dlx2-induced neuronal transdifferentiation. In contrast, the neurogenic competence of Ink4a/Arf-deficient astroglia is both greatly increased and does not diminish through serial cell culture passage. Electrophysiological analysis further demonstrates the neuronal identity of cells induced from Ink4a/Arf-null astroglia, and short hairpin RNA-mediated acute knockdown of p16Ink4a and p19Arf p16(Ink4a) and p19(Arf) indicates that these gene products function postnatally as a barrier to cellular transdifferentiation. Finally, we found that mouse fibroblasts deficient for Ink4a/Arf also exhibit greatly enhanced transcription factor-induced neuronal induction. These data indicate that Ink4a/Arf is a potent barrier to direct neuronal transdifferentiation and further suggest that this locus functions normally in the progressive developmental restriction of postnatal astrocytes.","journal":"J Neurosci","volume":"34","number":"37","pages":"12560–12567","month":"September","year":"2014","keywords":"Ink4a/Arf; astroglia; induced neuron; transcription factor; transdifferentiation","language":"en","bibtex":"@ARTICLE{Price2014-lp,\n title = \"The {Ink4a/Arf} locus is a barrier to direct neuronal\n transdifferentiation\",\n author = \"Price, James D and Park, Ki-Youb and Chen, Jiadong and Salinas,\n Ryan D and Cho, Mathew J and Kriegstein, Arnold R and Lim, Daniel\n A\",\n abstract = \"Non-neurogenic cell types, such as cortical astroglia and\n fibroblasts, can be directly converted into neurons by the\n overexpression of defined transcription factors. Normally, the\n cellular phenotype of such differentiated cells is remarkably\n stable and resists direct cell transdifferentiation. Here we show\n that the Ink4a/Arf (also known as Cdkn2a) locus is a\n developmental barrier to direct neuronal transdifferentiation\n induced by transcription factor overexpression. With serial\n passage in vitro, wild-type postnatal cortical astroglia become\n progressively resistant to Dlx2-induced neuronal\n transdifferentiation. In contrast, the neurogenic competence of\n Ink4a/Arf-deficient astroglia is both greatly increased and does\n not diminish through serial cell culture passage.\n Electrophysiological analysis further demonstrates the neuronal\n identity of cells induced from Ink4a/Arf-null astroglia, and\n short hairpin RNA-mediated acute knockdown of p16Ink4a and p19Arf\n p16(Ink4a) and p19(Arf) indicates that these gene products\n function postnatally as a barrier to cellular\n transdifferentiation. 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