Nerve growth factor‐mediated collateral sprouting of central sensory axons into deafferentated regions of the dorsal horn is enhanced in the absence of the p75 neurotrophin receptor

Abstract

This study examined the growth capacity of nerve growth factor (NGF)-responsive dorsal root ganglion (DRG) central processes using mice of the following genotypes: wildtype, p75 neurotrophin receptor (p75NTR) exon III null mutant, NGF transgenic, and NGF transgenic with p75NTR exon III null mutation (NGF/p75(-/-)). In wildtype and p75NTR exon III null mutant mice calcitonin gene-related peptide (CGRP) immunoreactivity in the dorsal horn is dramatically reduced at both 3 and 28 days after rhizotomy. NGF transgenic and NGF/p75(-/-) mice also display reduced CGRP immunoreactivity 3 days after rhizotomy, but by postsurgical day 28 significant increases in the density of CGRP-positive axons are observed in the injured dorsal horns of these mice. Interestingly, NGF/p75(-/-) mice displayed significantly more new axonal growth when compared to NGF transgenic mice expressing full-length p75NTR. Immunohistochemical and ultrastructural analyses revealed that this axonal growth is not the result of regeneration but rather injury-induced sprouting by intact DRG central processes into the lesion site. This collateral growth is restricted to deafferentated areas of the dorsal horn, and we therefore propose that this is an example of compensatory sprouting by NGF-sensitive axons in the spinal cord, a response that is enhanced in the absence of NGF binding to p75NTR.

p75NTR expression in rat urinary bladder sensory neurons and spinal cord with cyclophosphamide‐induced cystitis

“…Previous studies have suggested a role for p75 NTR in both restraining and facilitating axonal growth in the dorsal horn after dorsal rhizotomy, spinal cord injury and during development (Hannila and Kawaja, 2005;Scott et al, 2005). p75 NTR expression and upregulation with CYPinduced cystitis in the lumbosacral DH may represent central projections of sensory neurons, terminals of projection neurons, and/or descending p75 NTR systems (Pioro and Cuello, 1990;Sobreviela et al, 1994) exhibiting p75 NTR -IR, whereas interneuronal expression of p75 NTR is less likely (Bothwell, 1995).…”

“…Although numerous studies have suggested a central or peripheral role for p75 NTR after axotomy (Wakabayashi et al, 1998;Keast and Kepper, 2001;Hannila and Kawaja, 2005;Scott et al, 2005;Obata et al, 2006) or peripheral somatic inflammation (Cho et al, 1996;Pezet et al, 2001;Chien et al, 2007), few studies have examined the role of p75 NTR in normal or inflamed lower urinary tract pathways (Wakabayashi et al, 1996(Wakabayashi et al, , 1998(Wakabayashi et al, , 2002Vaidy- anathan Elsasser-Beile et al, 2000;Jahed and Kawaja, 2005;Tong and Cheng, 2005). To our knowledge, no studies have examined changes in p75 NTR expression in central or peripheral micturition reflex pathways after bladder inflammation.…”

“…Although p75 NTR has been shown to increase binding affinity of TrkA for NGF and increase the activities of the TrkA receptor in some systems (Chao and Hempstead, 1995), p75 NTR may also hinder TrkA binding to NGF by sequestering increased amounts of NGF, leaving less available to bind TrkA (Hannila and Kawaja, 2005;Nykjaer et al, 2005;Dhanoa et al, 2006). Previous studies have demonstrated that expression of p75 NTR and TrkA can result in synergistic and antagonistic functions (Schweigreiter, 2006).…”

Role of p75NTR in female rat urinary bladder with cyclophosphamide-induced cystitis

“…Whereas it is known that p75 NTR expression can enhance TrkA-NGF binding in some systems (1,9), p75 NTR may also reduce NGF-TrkA signaling by sequestering NGF (19,31,46). In the latter instance, any decrease or perturbation in NGF/ p75 NTR binding may tip the homeostatic equilibrium, resulting in increased NGF bioavailability to enhance NGF/TrkA signaling.…”

The p75 neurotrophin receptor: at the crossroad of neural repair and death

“…For example, expression of the p75 NTR in proliferating satellite glia in the injured dorsal root ganglion (DRG) correlates with the appearance of sympathetic sprouting which is attenuated in p75 NTR null mice (Hannila and Kawaja, 2005). In studies of motor neuron injury, less motor neuron survival was seen after the introduction of grafted Schwann cells deficient in p75 NTR (Tomita et al, 2007).…”