Abstract
BackgroundIn the developing vertebrate peripheral nervous system, the survival of sympathetic neurons and the majority of sensory neurons depends on a supply of nerve growth factor (NGF) from tissues they innervate. Although neurotrophic theory presupposes, and the available evidence suggests, that the level of NGF expression is completely independent of innervation, the possibility that innervation may regulate the timing or level of NGF expression has not been rigorously investigated in a sufficiently well-characterized developing system.ResultsTo address this important question, we studied the influence of innervation on the regulation of NGF mRNA expression in the embryonic mouse maxillary process in vitro and in vivo. The maxillary process receives its innervation from predominantly NGF-dependent sensory neurons of the trigeminal ganglion and is the most densely innervated cutaneous territory with the highest levels of NGF in the embryo. When early, uninnervated maxillary processes were cultured alone, the level of NGF mRNA rose more slowly than in maxillary processes cultured with attached trigeminal ganglia. In contrast to the positive influence of early innervation on NGF mRNA expression, the levels of brain-derived neurotrophic factor (BDNF) mRNA and neurotrophin-3 (NT3) mRNA rose to the same extent in early maxillary processes grown with and without trigeminal ganglia. The level of NGF mRNA, but not BDNF mRNA or NT3 mRNA, was also significantly lower in the maxillary processes of erbB3-/- mice, which have substantially fewer trigeminal neurons than wild-type mice.ConclusionsThis selective effect of initial innervation on target field NGF mRNA expression provokes a re-evaluation of a key assertion of neurotrophic theory that the level of NGF expression is independent of innervation.
Highlights
In the developing vertebrate peripheral nervous system, the survival of sympathetic neurons and the majority of sensory neurons depends on a supply of nerve growth factor (NGF) from tissues they innervate
Influence of innervation on neurotrophin expression in vitro We began investigating the influence of innervation on neurotrophin expression by culturing early maxillary processes with and without attached trigeminal ganglia
The levels of NGF, brain-derived neurotrophic factor (BDNF) and NT3 mRNAs in the innervated and uninnervated maxillary process explants were quantified using a very sensitive competitive RTPCR method [14]. The levels of these transcripts are expressed relative to the level of the mRNA for the house-keeping enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) to correct for any small differences in the size of dissected tissue. These cultures were set up at stages when the earliest trigeminal axons reach and begin to innervate the maxillary process in vivo, namely, at E10.5 when small numbers of trigeminal axons are starting to grow into the maxillary mesenchyme and at E11 when the first axons come into proximity with the maxillary epithelium [10], where the highest levels of NGF mRNA are expressed later in development [8]
Summary
In the developing vertebrate peripheral nervous system, the survival of sympathetic neurons and the majority of sensory neurons depends on a supply of nerve growth factor (NGF) from tissues they innervate. The targets produce just the right amount of neurotrophic factor to support the required number of neurons, and superfluous neurons are eliminated in a phase of cell death shortly after the onset of target innervation [1]. NGF has been shown to be produced in the targets of NGF-dependent neurons in proportion to their final innervation density, experimental manipulation of the availability of NGF during development influences the number of NGF-dependent neurons that survive and target-derived NGF is retrogradely transported in endosomes that generate survival signals in cell bodies of the innervating neurons [2,3,4]. The developmental rise in ventricular NGF mRNA is unaffected by sympathectomy part way through this rise [6]
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