The expression of prosaposin and its receptors, GRP37 and GPR37L1, are increased in the developing dorsal root ganglion.
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ABSTRACT:
SUBMITTER: Taniguchi M
PROVIDER: S-EPMC8357083 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Osteopontin expression has previously been demonstrated in the adult rat dorsal root ganglion, although its function remains unclear. Here, we demonstrate, using real-time reverse transcription-polymerase (RT-PCR) chain reaction, that osteopontin mRNA expression is increased 1 and 3 weeks following sciatic nerve section (axotomy). Further, immunohistochemical staining suggests that this increase is restricted to neurons already expressing the protein. Osteopontin knock-out animals have significantly increased mechanosensory thresholds in the intact adult compared with the wild-type controls; however no differences in allodynia are noted between genotypes using a model of neuropathic pain. Lastly, exogenous recombinant osteopontin has no effect on neurite outgrowth from adult wild-type sensory neurons, nor were differences in neurite outgrowth observed in osteopontin knock-out animals compared with wild-type controls.
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Project description:Discovery of neuroprotective pathways is one of the major priorities for neuroscience. Astrocytes are natural neuroprotectors and it is likely that brain resilience can be enhanced by mobilizing their protective potential. Among G-protein coupled receptors expressed by astrocytes, two highly related receptors, GPR37L1 and GPR37, are of particular interest. Previous studies suggested that these receptors are activated by a peptide Saposin C and its neuroactive fragments (prosaptide TX14(A)), which were demonstrated to be neuroprotective in various animal models by several groups. However, pairing of Saposin C or prosaptides with GPR37L1/GPR37 has been challenged and presently GPR37L1/GPR37 have regained their orphan status. Here, we demonstrate that in their natural habitat, astrocytes, these receptors mediate a range of effects of TX14(A), including protection from oxidative stress. The Saposin C/GPR37L1/GPR37 pathway is also involved in the neuroprotective effect of astrocytes on neurons subjected to oxidative stress. The action of TX14(A) is at least partially mediated by Gi-proteins and the cAMP-PKA axis. On the other hand, when recombinant GPR37L1 or GPR37 are expressed in HEK293 cells, they are not functional and do not respond to TX14(A), which explains unsuccessful attempts to confirm the ligand-receptor pairing. Therefore, this study identifies GPR37L1/GPR37 as the receptors for TX14(A), and, by extension of Saposin C, and paves the way for the development of neuroprotective therapeutics acting via these receptors.
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Project description:Neuropathic pain is a chronic condition that occurs frequently after nerve injury and induces hypersensitivity or allodynia characterized by aberrant neuronal excitability in the spinal cord dorsal horn. Fibronectin leucine-rich transmembrane protein 3 (FLRT3) is a modulator of neurite outgrowth, axon pathfinding, and cell adhesion, which is upregulated in the dorsal horn following peripheral nerve injury. However, the function of FLRT3 in adults remains unknown. Therefore, we aimed to investigate the involvement of spinal FLRT3 in neuropathic pain using rodent models. In the dorsal horns of male rats, FLRT3 protein levels increased at day 4 after peripheral nerve injury. In the DRG, FLRT3 was expressed in activating transcription factor 3-positive, injured sensory neurons. Peripheral nerve injury stimulated Flrt3 transcription in the DRG but not in the spinal cord. Intrathecal administration of FLRT3 protein to naive rats induced mechanical allodynia and GluN2B phosphorylation in the spinal cord. DRG-specific FLRT3 overexpression using adeno-associated virus also produced mechanical allodynia. Conversely, a function-blocking FLRT3 antibody attenuated mechanical allodynia after partial sciatic nerve ligation. Therefore, FLRT3 derived from injured DRG neurons increases dorsal horn excitability and induces mechanical allodynia.SIGNIFICANCE STATEMENT Neuropathic pain occurs frequently after nerve injury and is associated with abnormal neuronal excitability in the spinal cord. Fibronectin leucine-rich transmembrane protein 3 (FLRT3) regulates neurite outgrowth and cell adhesion. Here, nerve injury increased FLRT3 protein levels in the spinal cord dorsal root, despite the fact that Flrt3 transcripts were only induced in the DRG. FLRT3 protein injection into the rat spinal cord induced mechanical hypersensitivity, as did virus-mediated FLRT3 overexpression in DRG. Conversely, FLRT3 inhibition with antibodies attenuated mechanically induced pain after nerve damage. These findings suggest that FLRT3 is produced by injured DRG neurons and increases neuronal excitability in the dorsal horn, leading to pain sensitization. Neuropathic pain induction is a novel function of FLRT3.
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