title: The Ink4a/Arf locus is a barrier to direct neuronal transdifferentiation.
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.
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Developmental and Stem Cell Biology Graduate Program, Department of Neurological Surgery.
authors.forename: James D
authors.initials: JD
authors.lastname: Price
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Neurological Surgery.
authors.forename: Ki-Youb
authors.initials: KY
authors.lastname: Park
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Neurology, and.
authors.forename: Jiadong
authors.initials: J
authors.lastname: Chen
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Neurological Surgery.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Salinas
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Neurological Surgery.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Cho
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Neurology, and.
authors.forename: Arnold R
authors.initials: AR
authors.lastname: Kriegstein
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Developmental and Stem Cell Biology Graduate Program, Department of Neurological Surgery, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, California 94143 Limd@neurosurg.ucsf.edu.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lim
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16
keywords: Ink4a/Arf; astroglia; induced neuron; transcription factor; transdifferentiation