title: A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program.
abstract: The regenerative capacity of the injured CNS in adult mammals is severely limited, yet axons in the peripheral nervous system (PNS) regrow, albeit to a limited extent, after injury. We reasoned that coordinate regulation of gene expression in injured neurons involving multiple pathways was central to PNS regenerative capacity. To provide a framework for revealing pathways involved in PNS axon regrowth after injury, we applied a comprehensive systems biology approach, starting with gene expression profiling of dorsal root ganglia (DRGs) combined with multi-level bioinformatic analyses and experimental validation of network predictions. We used this rubric to identify a drug that accelerates DRG neurite outgrowth in vitro and optic nerve outgrowth in vivo by inducing elements of the identified network. The work provides a functional genomics foundation for understanding neural repair and proof of the power of such approaches in tackling complex problems in nervous system biology.
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Vijayendran
authors.initials: V
authors.lastname: Chandran
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Homaira
authors.initials: H
authors.lastname: Nawabi
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Takao
authors.initials: T
authors.lastname: Omura
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Revital
authors.initials: R
authors.lastname: Versano
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Huebner
authors.affiliation: Interdepartmental Program in Neuroscience, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Zhang
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Costigan
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Yekkirala
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Barrett
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Armin
authors.initials: A
authors.lastname: Blesch
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Izhak
authors.initials: I
authors.lastname: Michaelevski
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Davis-Turak
authors.affiliation: Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Fuying
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biostatistics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Langfelder
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biostatistics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Horvath
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: He
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Larry
authors.initials: L
authors.lastname: Benowitz
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Mike
authors.initials: M
authors.lastname: Fainzilber
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Tuszynski
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.affiliation: Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: dhg@mednet.ucla.edu.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D001369:Axons / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000166:cytology*; D005786:Gene Expression Regulation / Q000235:genetics; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D007473:Ion Channels; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology*; D019884:Nitrogenous Group Transferases / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000503:physiopathology*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C506911:FXYD5 protein, mouse; D007473:Ion Channels; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; C544766:TROP2 protein, mouse; D019884:Nitrogenous Group Transferases; C488523:Gfpt1 protein, mouse; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D051059:PTEN Phosphohydrolase; D020764:cdc42 GTP-Binding Protein