A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program

Vijayendran Chandran; Giovanni Coppola; Homaira Nawabi; Takao Omura; Revital Versano; Eric A Huebner; Alice Zhang; Michael Costigan; Ajay Yekkirala; Lee Barrett; Armin Blesch; Izhak Michaelevski; Jeremy Davis-Turak; Fuying Gao; Peter Langfelder; Steve Horvath; Zhigang He; Larry Benowitz; Mike Fainzilber; Mark Tuszynski; Clifford J Woolf; Daniel H Geschwind

doi:10.1016/j.neuron.2016.01.034

A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth Program

Neuron. 2016 Mar 2;89(5):956-70. doi: 10.1016/j.neuron.2016.01.034. Epub 2016 Feb 18.

Authors

Vijayendran Chandran¹, Giovanni Coppola², Homaira Nawabi³, Takao Omura³, Revital Versano¹, Eric A Huebner³, Alice Zhang⁴, Michael Costigan³, Ajay Yekkirala³, Lee Barrett³, Armin Blesch⁵, Izhak Michaelevski⁶, Jeremy Davis-Turak¹, Fuying Gao⁷, Peter Langfelder⁸, Steve Horvath⁸, Zhigang He³, Larry Benowitz³, Mike Fainzilber⁶, Mark Tuszynski⁵, Clifford J Woolf³, Daniel H Geschwind⁹

Affiliations

¹ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² 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.
³ F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁴ Interdepartmental Program in Neuroscience, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
⁶ Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel.
⁷ 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.
⁸ 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.
⁹ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Antigens, Neoplasm / genetics
Antigens, Neoplasm / metabolism
Axons / physiology*
Cell Adhesion Molecules / genetics
Cell Adhesion Molecules / metabolism
Cells, Cultured
Chromatin Immunoprecipitation
Disease Models, Animal
Ganglia, Spinal / cytology*
Gene Expression Regulation / genetics
Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
Ion Channels
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Microfilament Proteins
Nerve Regeneration / genetics
Nerve Regeneration / physiology*
Neurons / cytology*
Nitrogenous Group Transferases / genetics
Nitrogenous Group Transferases / metabolism
PTEN Phosphohydrolase / genetics
PTEN Phosphohydrolase / metabolism
Peripheral Nervous System Diseases / physiopathology*
cdc42 GTP-Binding Protein / genetics
cdc42 GTP-Binding Protein / metabolism

Substances

Antigens, Neoplasm
Cell Adhesion Molecules
FXYD5 protein, mouse
Ion Channels
Membrane Glycoproteins
Membrane Proteins
Microfilament Proteins
TROP2 protein, mouse
Nitrogenous Group Transferases
Gfpt1 protein, mouse
Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)
PTEN Phosphohydrolase
cdc42 GTP-Binding Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding