title: Progranulin promotes peripheral nerve regeneration and reinnervation: role of notch signaling.
abstract: Peripheral nerve injury is a frequent cause of lasting motor deficits and chronic pain. Although peripheral nerves are capable of regrowth they often fail to re-innervate target tissues.
  
  
  
  Using newly generated transgenic mice with inducible neuronal progranulin overexpression we show that progranulin accelerates axonal regrowth, restoration of neuromuscular synapses and recovery of sensory and motor functions after injury of the sciatic nerve. Oppositely, progranulin deficient mice have long-lasting deficits in motor function tests after nerve injury due to enhanced losses of motor neurons and stronger microglia activation in the ventral horn of the spinal cord. Deep proteome and gene ontology (GO) enrichment analysis revealed that the proteins upregulated in progranulin overexpressing mice were involved in 'regulation of transcription' and 'response to insulin' (GO terms). Transcription factor prediction pointed to activation of Notch signaling and indeed, co-immunoprecipitation studies revealed that progranulin bound to the extracellular domain of Notch receptors, and this was functionally associated with higher expression of Notch target genes in the dorsal root ganglia of transgenic mice with neuronal progranulin overexpression. Functionally, these transgenic mice recovered normal gait and running, which was not achieved by controls and was stronger impaired in progranulin deficient mice.
  
  
  
  We infer that progranulin activates Notch signaling pathways, enhancing thereby the regenerative capacity of partially injured neurons, which leads to improved motor function recovery.
authors: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors: Christine
authors: C
authors: Altmann
authors: Molecular Signal Transduction Laboratories, Institute for Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: Verica
authors: V
authors: Vasic
authors: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors: Stefanie
authors: S
authors: Hardt
authors: Functional Proteomics, SFB815 Core Unit, Goethe-University, Frankfurt, Germany.
authors: Juliana
authors: J
authors: Heidler
authors: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
authors: Annett
authors: A
authors: Häussler
authors: Functional Proteomics, SFB815 Core Unit, Goethe-University, Frankfurt, Germany.
authors: Ilka
authors: I
authors: Wittig
authors: Molecular Signal Transduction Laboratories, Institute for Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
authors: Mirko H H
authors: MHH
authors: Schmidt
authors: Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany. tegeder@em.uni-frankfurt.de.
authors: Irmgard
authors: 0000-0001-7524-8025
authors: I
authors: Tegeder
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D000077155:Granulins; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000502:physiology*; D059348:Peripheral Nerve Injuries / Q000378:metabolism*; D000077153:Progranulins; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology; D012584:Sciatic Nerve / Q000293:injuries; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000077155:Granulins; C120204:Grn protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D051880:Receptors, Notch
keywords: Locomotion; Motor neuron; Nerve injury; Notch; Progranulin; Proteomics