A role for p75 receptor in neurotrophin-3 functioning during the development of limb proprioception

Neurotrophin-3 is indispensable for the development of limb proprioceptive neurons and their end organs, muscle spindles. To determine whether the low-affinity p75 receptor potentiates the actions of neurotrophin-3, we examined the development of the proprioceptive system in p75 null mutant mice that had either normal or decreased tissue levels of neurotrophin-3. Postnatal mice lacking both copies of the p75 gene had fewer sensory neurons in dorsal root ganglia, but normal complements of muscle spindles in fast hindlimb muscles, although the slow soleus muscle showed a 50% loss of spindles. However, compound mutants lacking both copies of the p75 gene as well as one copy of the neurotrophin-3 gene displayed a dystonic/ataxic phenotype similar to that observed previously in neurotrophin-3 null mutants devoid of proprioception. The compound mutants also exhibited a commensurate loss of parvalbumin-expressing (proprioceptive) neurons in dorsal root ganglia. The degree of deficiency of spindles (and presumably proprioceptive neurons) in the compound mutants exceeded the sum of deficits in single mutants lacking either both copies of p75 genes or one copy of neurotrophin-3 gene, suggesting a synergistic interaction between the p75 receptor and neurotrophin-3. Neuronal deficits in the compound mutants were present prior to embryonic day 14, indicating an early role for the p75 receptor in sensory neuronogenesis. Collectively, these data indicate that the p75 receptor is not essential for the survival and differentiation of most limb proprioceptive neurons when neurotrophin-3 is expressed at normal levels. However, the p75 receptor may act in synergy with neurotrophin-3 to enhance the survival of proprioceptive neurons when tissue levels of neurotrophin-3 are a limiting factor.