Nerve growth factor (NGF) and its precursor proNGF are perhaps the best described growth factors of the mammalian nervous system. There remains, however, a paucity of information regarding the precise cellular sites of proNGF/NGF synthesis. Here we report the generation of transgenic mice in which the NGF promoter controls the ectopic synthesis of enhanced green fluorescent protein (EGFP). These transgenic mice provide an unprecedented resolution of both neural cells (e.g., neocortical and hippocampal neurons) and non-neural cells (e.g., renal interstitial cells and thymic reticular cells) that display NGF promoter activity from postnatal development to adulthood. Moreover, the transgene is inducible by injury. At 2 days after sciatic nerve ligation, a robust population of EGFP-positive cells is seen in the proximal nerve stump. These transgenic mice offer novel insights into the cellular sites of NGF promoter activity and can be used as models for investigating the regulation of proNGF/NGF expression after injury. INDEXING TERMSneurotrophin; nerve growth factor; transgene; brain; peripheral nerve; injury Nerve growth factor (NGF), one of several neurotrophins of the vertebrate nervous system, was first localized in the male mouse submaxillary gland (Levi-Montalcini and Cohen, 1960). Later studies found that sympathetic ganglia, as well as target sites of sympathetic innervation (e.g., irides, heart atria, and prostate), have detectable levels of NGF mRNA and protein (Korsching and Thoenen, 1983a;Heumann et al., 1984;Shelton and Reichardt, 1984). The presence of NGF protein in sympathetic neurons has been linked to the binding and retrograde transport of this neurotrophin from target tissues, rather than to endogenous CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptsynthesis by ganglionic neurons (or adjacent glia) (Hendry et al., 1974;Stöckel et al., 1976;Johnson et al., 1978).Intracerebral injections of iodinated NGF into selected sites, including the neocortex and hippocampus, revealed that the basal forebrain cholinergic neurons are capable of binding and retrogradely transporting NGF (Seiler and Schwab, 1984). This observation suggested that endogenous NGF might be utilized by these central projection neurons, in a manner similar to how NGF is acquired by sympathetic neurons from their peripheral target tissues. In the rat brain, levels of NGF mRNA are, in fact, highest in the neocortex and hippocampus, and select neuronal populations in both these central sites display NGF mRNA expression and protein synthesis (Korsching et al., 1985;Shelton and Reichardt, 1986;Whittemore et al., 1986;Ernfors et al., 1990;Lauterborn et al., 1991;. Detection of NGF mRNA by in situ hybridization and NGF protein by immunostaining elsewhere in the mammalian brain led to both complementary (e.g., in the basal forebrain) and conflicting (e.g., in the striatum) observations. Other methods are needed to provide further insight into the central sources of NGF synthesis (during normal development and as ...

Elevating levels of nerve growth factor (NGF) can have pronounced effects on the survival and maintenance of distinct populations of neurons. We have generated a line of transgenic mice in which NGF is expressed under the control of the smooth muscle α-actin promoter. These transgenic mice have augmented levels of NGF protein in the descending colon and urinary bladder, so these tissues display increased densities of NGF-sensitive sympathetic efferents and sensory afferents. Here we provide a thorough examination of sympathetic and sensory axonal densities in the descending colon and urinary bladder of NGF transgenic mice with and without the expression of the p75 neurotrophin receptor (p75NTR). In response to elevated NGF levels, sympathetic axons (immunostained for tyrosine hydroxylase) undergo robust collateral sprouting in the descending colon and urinary bladder of adult transgenic mice (i.e., those tissues having smooth muscle cells); this sprouting is not augmented in the absence of p75NTR expression. As for sensory axons (immunostained for calcitonin gene-related peptide) in the urinary bladders of transgenic mice, fibers undergo sprouting that is further increased in the absence of p75NTR expression. Sympathetic axons are also seen invading the sensory ganglia of transgenic mice; these fibers form perineuronal plexi around a subpopulation of sensory somata. Our results reveal that elevated levels of NGF in target tissues stimulate sympathetic and sensory axonal sprouting and that an absence of p75NTR by sensory afferents (but not by sympathetic efferents) leads to a further increase of terminal arborization in certain NGF-rich peripheral tissues.