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The p75 neurotrophin receptor (p75NTR ) is required for maintaining peripheral sensory neuron survival and function; however, the underlying cellular mechanism remains unclear. The general view is that expression of p75NTR by the neuron itself is required for maintaining sensory neuron survival and myelination in the peripheral nervous system (PNS). Adopting a neuronal-specific conditional knockout strategy, we demonstrate the partial depletion of p75NTR in neurons exerts little influence upon maintaining sensory neuron survival and peripheral nerve myelination in health and after demyelinating neuropathy. Our data show that the density and total number of dorsal root ganglion (DRG) neurons in 2-month-old mice is not affected following the deletion of p75NTR in large-diameter myelinating neurons, as assessed by stereology. Adopting experimental autoimmune neuritis induced in adult male mice, an animal model of demyelinating peripheral neuropathy, we identify that deleting p75NTR in myelinating neurons exerts no influence upon the disease progression, the total number of DRG neurons, and the extent of myelin damage in the sciatic nerve, indicating that the expression of neuronal p75NTR is not essential for maintaining peripheral neuron survival and myelination after a demyelinating insult in vivo. Together, results of this study suggest that the survival and myelination of peripheral sensory neurons is independent of p75NTR expressed by a subtype of neurons in vivo. Thus, our findings provide new insights into the mechanism underpinning p75NTR -mediated neuronal survival in the PNS.

The number of cells generated by a proliferating stem or precursor cell can be influenced both by proliferation and by the degree of cell death/survival of the progeny generated. In this study, the extent to which cell survival controls progenitor number was examined by comparing the growth characteristics of neurosphere cultures derived from mice lacking genes for the death-inducing Bcl-2 homologue Hara Kiri (Hrk), apoptosis-associated protein 1 (Apaf1), or the prosurvival nuclear factor-kappaB (NFkappaB) subunits p65, p50, or c-rel. We found no evidence that Hrk or Apaf1, and by inference the mitochondrial cell death pathway, are involved in regulating the number of neurosphere-derived progeny. However, we identified the p65p50 NFkappaB dimer as being required for the normal growth and expansion of neurosphere cultures. Genetic loss of both p65 and p50 NFkappaB subunits resulted in a reduced number of progeny but an increased proportion of neurons. No effect on cell survival was observed. This suggests that the number and fate of neural progenitor cells are more strongly regulated by cell cycle control than survival.

The 75 kD low-affinity neurotrophin receptor (p75(NTR)) is expressed in developing and axotomised spinal motor neurons. There is now convincing evidence that p75(NTR) can, under some circumstances, become cytotoxic and promote neuronal cell death. We report here that a single application of antisense p75(NTR) oligodeoxynucleotides to the proximal nerve stumps of neonatal rats significantly reduces the loss of axotomised motor neurons compared to controls treated with nonsense oligodeoxynucleotides or phosphate-buffered saline. Our investigations also show that daily systemic intraperitoneal injections of antisense p75(NTR) oligodeoxynucleotides for 14 days significantly reduce the loss of axotomised motor neurons compared to controls. Furthermore, we found that systemic delivery over a similar period continues to be effective following axotomy when intraperitoneal injections were 1) administered after a delay of 24 hr, 2) limited to the first 7 days, or 3) administered every third day. In addition, p75(NTR) protein levels were reduced in spinal motor neurons following treatment with antisense p75(NTR) oligodeoxynucleotides. There were also no obvious side effects associated with antisense p75(NTR) oligodeoxynucleotide treatments as determined by behavioural observations and postnatal weight gain. Our findings indicate that antisense-based strategies could be a novel approach for the prevention of motor neuron degeneration associated with injuries or disease.