It is well known that p75 knockout (p75KO) mice exhibit reduced heat sensitivity. This phenotype has been mainly attributed to a ~50% loss of sensory neurons from the dorsal root ganglia (DRG) during development, which was supported by a 2-3 fold decrease in NGF sensitivity of p75KO sensory neurons, when they are cultured in isolation without Schwann cells (SC). Besides having an effect on cell survival, p75 also had an impact on functionality of defined sensory subtypes, wherein the loss of p75 reduced the mechanical responsiveness of C-fibers and D-hair receptors as well as the heat sensitivity of A-fiber nociceptors in in vitro skin-nerve preparations. Surprisingly, our preliminary data from conditional p75 knockout mice illustrate that p75 influences nociception through its role in SC rather than from sensory neurons. These unexpected results are reminiscent of a report that demonstrated nociceptive defects due to a loss of sensory neurons, upon blocking ErbB receptor signaling or FGF receptor signaling in non-myelinating SC. Indeed, our preliminary data illustrate that there exists crosstalk between p75 and ErbB2 in response to BDNF in SC. Thus, we propose to investigate the role that p75 plays in nociception, using conditional knockout mice in which p75 is selectively deleted in SC or sensory neurons.
P75 is a neurotrophin receptor that plays a role in nociception. A defect in nociception contributes to peripheral neuropathy, of which ~70% result from diabetes according to the Foundation for Peripheral Neuropathy. The incidence of peripheral neuropathy is expected to increase dramatically, since as many as 1 in 3 American adults will be diagnosed with type-2 diabetes by 2050 according to the American Diabetes Association. In contrast to a long-held belief that p75 influences nociception by regulating sensory neuron function, our preliminary study suggests that it plays a role in nociception by regulating properties of myelinating Schwann cells. With these novel results, we here propose to characterize the role of p75 individually in sensory neurons and in Schwann cells.
| Ryu, Jae Cheon; Tooke, Katharine; Malley, Susan E et al. (2018) Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury. J Clin Invest 128:1772-1786 |
