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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