A role for p75 receptor in neurotrophin-3 functioning during the development of limp 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 examin ed the development of the proprioceptive system in p75 null mutant mice tha t had either normal or decreased tissue levels of neurotrophin-3. Postnatal mice lacking both copies of the p75 gene had fewer sensory neurons in dors al root ganglia, but normal complements of muscle spindles in fast hindlimb muscles, although the slow soleus muscle showed a 50% loss of spindles. Ho wever, compound mutants lacking both copies of the p75 gene as well as one copy of the neurotrophin-3 gene displayed a dystonic/ataxic phenotype simil ar to that observed previously in neurotrophin-3 null mutants devoid of pro prioception. The compound mutants also exhibited a commensurate loss of par valbumin-expressing (proprioceptive) neurons in dorsal root ganglia. The de gree of deficiency of spindles land presumably proprioceptive neurons) in t he compound mutants exceeded the sum of deficits in single mutants lacking either both copies of p75 genes or one copy of neurotrophin-3 gene, suggest ing a synergistic interaction between the p75 receptor and neurotrophin-3. Neuronal deficits in the compound mutants were present prier to embryonic d ay 14, indicating an early role for the p75 receptor in sensory neuronogene sis. Collectively, these data indicate that the p75 receptor is not essential fo r the survival and differentiation of most limb proprioceptive neurons when neurotrophin-3 is expressed at normal levels. However, the p75 receptor ma y act in synergy with neurotrophin-3 to enhance the survival of propriocept ive neurons when tissue levels of neurotrophin-3 are a limiting factor. (C) 1999 IBRO. Published by Elsevier Science Ltd.