Abstract
Neurotrophin-3 (NT-3) is a target-derived neurotrophic factor that regulates sensory neuronal survival and growth. Here we report that NT-3 plays a critical permissive role in cutaneous sensory nerve sprouting that contributes to pain and sensitivity following skin wounding in young animals. Sensory terminal sprouting in neonatally wounded dermis and epidermis is accompanied by increased NT-3 transcription, NT-3 protein levels, and NT-3 protein release 3-7days post skin injury in newborn rats and mice. Functional blockade of NT-3 activity with specific antibodies greatly reduces sensory neurite outgrowth induced by wounded skin, but not by naïve skin, in dorsal root ganglion/skin co-cultures. The requirement for NT-3 for sensory terminal sprouting in vivo is confirmed by the absence of wound-induced hyperinnervation in heterozygous transgenic mice (NT-3+/−lacZ). We conclude that upregulation of NT-3 in neonatally wounded skin is a critical factor mediating the sensory nerve sprouting that underlies hypersensitivity and pain following skin injury.
Highlights
The development of sensory innervation of the skin is highly dependent upon target-derived neurotrophins [43] that control the survival, development, and function of peripheral and central neurons [27]
Synthesis of nerve growth factor (NGF) in the developing epithelium begins with the arrival of sensory fibres [15], and its concentration in the skin is directly correlated with the final innervation density [23], of nociceptors [2,27,43], independent of its role in sensory neuron survival [14]
We have shown that NT-3 protein is upregulated and secreted from neonatally wounded skin and that this NT-3 stimulates growth of peripheral sensory nerve terminals, resulting in hyperinnervation of the wounded area
Summary
The development of sensory innervation of the skin is highly dependent upon target-derived neurotrophins [43] that control the survival, development, and function of peripheral and central neurons [27]. In the developing peripheral somatosensory system, limiting quantities of neurotrophins control the number of surviving sensory neurons and the target innervation density [16,27]. Synthesis of NGF in the developing epithelium begins with the arrival of sensory fibres [15], and its concentration in the skin is directly correlated with the final innervation density [23], of nociceptors [2,27,43], independent of its role in sensory neuron survival [14].
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