Abstract
BackgroundPeripheral 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.ResultsUsing 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.ConclusionWe infer that progranulin activates Notch signaling pathways, enhancing thereby the regenerative capacity of partially injured neurons, which leads to improved motor function recovery.Graphical abstract Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0132-1) contains supplementary material, which is available to authorized users.
Highlights
Peripheral nerve injury is a frequent cause of lasting motor deficits and chronic pain
Anti-Tumor necrosis factor alpha (TNFα) effects do not account for the neuroinflammatory phenotype of progranulin knockout mice [15] and are likely irrelevant for progranulin’s effects in the context of frontotemporal dementia, which is caused by loss-of-functions mutations in the progranulin gene
We found an increase of Notch-dependent genes, Hes and Hey in the Dorsal root ganglia (DRG) in progranulin overexpressing mice, again suggesting an enhancement of Notch-dependent gene transcription under these conditions
Summary
Peripheral nerve injury is a frequent cause of lasting motor deficits and chronic pain. Endogenous mechanisms exist, which counteract these maladaptive changes, helping to regain stability and function in the sensory and motor axis. Progranulin is a secretory cysteine-rich protein consisting in seven and a half granulins [10, 11], which is produced by neurons and immune cells of myeloid lineages including microglia [12] and likely acts as autocrine and paracrine growth factor. It is highly expressed in motor neurons [9] and in glia surrounding injured motor neurons [8]. The growth promoting effects of recombinant progranulin were independent of sortilin [16, 17], suggesting that sortilin only accepts endogenous progranulin or requires some help or pre-processing
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