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 t hat mediate mechanoreception and their Merkel cell containing touch dome en d organs (Airaksinen et al,, 1996), In this study we determined whether NT3 overexpressed in the skin could restore innervation lost when endogenous N T3 levels were reduced. Hybrid mice that overexpress NT3 in basal keratinoc ytes but lack one endogenous NT3 allele (K14-NT3/NT3(+/-)) were compared to NT3 overexpresser (K14-NT3) mice, heterozygous knockout (NT3(+/-)) mice, a nd littermate control mice. In line with previous analyses, NT3+/- mice los t 63% of the Merkel cells associated with touch domes, 67% of touch dome un its and the associated SAI innervation. All of these parameters were restor ed to overexpresser levels in K14-NT3/NT3+/- mice. Knockout NT3(+/-) mice a lso had a 31% reduction of L4/L5 dorsal root ganglion cells and a 24% reduc tion of myelinated axons in the saphenous cutaneous nerve. These losses wer e also restored in hybrid K14-NT3/NT3(+/-) mice, though only to control mou se values. These results indicate that overexpression of NT3 in skin of NT3 (+/-) knockout mice rescued most cutaneous neurons lost in NT3(+/-) mice, b ut was unable to rescue NT3-dependent neurons that project to noncutaneous sensory targets. (C) 2000 John Wiley & Sons, Inc. J Neurobiol 43: 40-49, 20 00.