title: Misexpression of ptf1a in cortical pyramidal cells in vivo promotes an inhibitory peptidergic identity.
abstract: The intracellular transcriptional milieu wields considerable influence over the induction of neuronal identity. The transcription factor Ptf1a has been proposed to act as an identity "switch" between developmentally related precursors in the spinal cord (Glasgow et al., 2005; Huang et al., 2008), retina (Fujitani et al., 2006; Dullin et al., 2007; Nakhai et al., 2007; Lelièvre et al., 2011), and cerebellum (Hoshino et al., 2005; Pascual et al., 2007; Yamada et al., 2014), where it promotes an inhibitory over an excitatory neuronal identity. In this study, we investigate the potency of Ptf1a to cell autonomously confer a specific neuronal identity outside of its endogenous environment, using mouse in utero electroporation and a conditional genetic strategy to misexpress Ptf1a exclusively in developing cortical pyramidal cells. Transcriptome profiling of Ptf1a-misexpressing cells using RNA-seq reveals that Ptf1a significantly alters pyramidal cell gene expression, upregulating numerous Ptf1a-dependent inhibitory interneuron markers and ultimately generating a gene expression profile that resembles the transcriptomes of both Ptf1a-expressing spinal interneurons and endogenous cortical interneurons. Using RNA-seq and in situ hybridization analyses, we also show that Ptf1a induces expression of the peptidergic neurotransmitter nociceptin, while minimally affecting the expression of genes linked to other neurotransmitter systems. Moreover, Ptf1a alters neuronal morphology, inducing the radial redistribution and branching of neurites in cortical pyramidal cells. Thus Ptf1a is sufficient, even in a dramatically different neuronal precursor, to cell autonomously promote characteristics of an inhibitory peptidergic identity, providing the first example of a single transcription factor that can direct an inhibitory peptidergic fate.
authors: Weill Cornell/Rockefeller University/Sloan Kettering Tri-Institutional MD-PhD Program, New York, New York 10065, Neuroscience Program, Weill Cornell Medical College, New York, New York 10065, Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065.
authors: Jeffrey B
authors: JB
authors: Russ
authors: Department of Neuroscience, UT Southwestern Medical Center, Dallas, Texas 75390, and.
authors: Mark D
authors: MD
authors: Borromeo
authors: Department of Neuroscience, UT Southwestern Medical Center, Dallas, Texas 75390, and.
authors: Rahul K
authors: RK
authors: Kollipara
authors: Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065.
authors: Praveen K
authors: PK
authors: Bommareddy
authors: Department of Neuroscience, UT Southwestern Medical Center, Dallas, Texas 75390, and.
authors: Jane E
authors: JE
authors: Johnson
authors: Neuroscience Program, Weill Cornell Medical College, New York, New York 10065, Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, Cell & Developmental Biology Program, Weill Cornell Medical College, New York, New York 10065 kaltschj@mskcc.org.
authors: Julia A
authors: JA
authors: Kaltschmidt
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology / Q000254:growth & development; D019295:Computational Biology; D018274:Electroporation; D004622:Embryo, Mammalian; D005136:Eye Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D018709:Statistics, Nonparametric; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome / Q000502:physiology*; D014404:Tubulin / Q000378:metabolism; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D005136:Eye Proteins; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; D010455:Peptides; D012097:Repressor Proteins; D014157:Transcription Factors; D014404:Tubulin; D000099260:Empty Spiracles Homeobox Proteins; C000605732:Pax6 protein, mouse; C462941:beta3 tubulin, mouse; C062602:transcription factor PTF1
keywords: Ptf1a; cortex; inhibitory interneuron; neuronal identity; peptidergic; subtype specification