Cutaneous overexpression of neurotrophin-3 (NT3) selectively restores sensory innervation in NT3 gene knockout mice.

Neurotrophin-3 (NT3) is essential for development of sensory innervation to the skin. NT3 supports the postnatal survival of primary sensory neurons that mediate mechanoreception and their Merkel cell containing touch dome end organs (Airaksinen et al., 1996). In this study we determined whether NT3 overexpressed in the skin could restore innervation lost when endogenous NT3 levels were reduced. Hybrid mice that overexpress NT3 in basal keratinocytes but lack one endogenous NT3 allele (K14-NT3/NT3(+/-)) were compared to NT3 overexpresser (K14-NT3) mice, heterozygous knockout (NT3(+/-)) mice, and littermate control mice. In line with previous analyses, NT3(+/-) mice lost 63% of the Merkel cells associated with touch domes, 67% of touch dome units and the associated SAI innervation. All of these parameters were restored to overexpresser levels in K14-NT3/NT3(+/-) mice. Knockout NT3(+/-) mice also had a 31% reduction of L4/L5 dorsal root ganglion cells and a 24% reduction of myelinated axons in the saphenous cutaneous nerve. These losses were also restored in hybrid K14-NT3/NT3(+/-) mice, though only to control mouse values. These results indicate that overexpression of NT3 in skin of NT3(+/-) knockout mice rescued most cutaneous neurons lost in NT3(+/-) mice, but was unable to rescue NT3-dependent neurons that project to noncutaneous sensory targets.