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Journal of Neuroscience, Vol 14, 1422-1432, Copyright © 1994 by Society for Neuroscience
Overexpression of nerve growth factor in epidermis of transgenic mice causes hypertrophy of the peripheral nervous system
KM Albers, DE Wright and BM Davis
Department of Pathology, University of Kentucky College of Medicine, Lexington 40536.
Survival of developing neurons is dependent on access to a limited supply
of target-derived neurotrophic factors. NGF is the most extensively
characterized of these molecules and during development is synthesized by
neuronal and nonneuronal target tissues such as the skin. To investigate
how target-derived NGF affects neuron survival and development of the PNS,
we used an epidermal-specific gene promoter to produce transgenic mice that
overexpress the mouse NGF cDNA in skin. Analysis of transgenic skin mRNA
synthesis by Northern and in situ hybridizations showed increased levels of
transgene-derived mRNA in the epidermis and associated hair follicles. The
increase in NGF mRNA correlated with a hypertrophy of peripheral sensory
and sympathetic nerves. Immunological analysis of skin using an anti-150
kDa neurofilament antibody showed numerous large nerve bundles and fibers
coursing throughout the dermis. Increased numbers of nerve processes in the
transgenic skin had immunoreactivity for calcitonin gene-related peptide
and tyrosine hydroxylase, indicating that both the sensory and sympathetic
systems were hypertrophied. The trigeminal and superior cervical ganglia
were greatly enlarged. Cell counts of trigeminal ganglia of control and
transgenic mice showed a 26-117% increase in the number of neurons in the
transgenics, indicating a reduction or total prevention of the program of
naturally occurring cell death. These results demonstrate that NGF
production by the epidermal target tissue controls neuronal survival, and
in so doing, establishes the level of innervation.
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