Abstract
BackgroundThe ability of a neuron to regenerate functional connections after injury is influenced by both its intrinsic state and also by extrinsic cues in its surroundings. Investigations of the transcriptional changes undergone by neurons during in vivo models of injury and regeneration have revealed many transcripts associated with these processes. Because of the complex milieu of interactions in vivo, these results include not only expression changes directly related to regenerative outgrowth and but also unrelated responses to surrounding cells and signals. In vitro models of neurite outgrowth provide a means to study the intrinsic transcriptional patterns of neurite outgrowth in the absence of extensive extrinsic cues from nearby cells and tissues.ResultsWe have undertaken a genome-wide study of transcriptional activity in embryonic superior cervical ganglia (SCG) and dorsal root ganglia (DRG) during a time course of neurite outgrowth in vitro. Gene expression observed in these models likely includes both developmental gene expression patterns and regenerative responses to axotomy, which occurs as the result of tissue dissection. Comparison across both models revealed many genes with similar gene expression patterns during neurite outgrowth. These patterns were minimally affected by exposure to the potent inhibitory cue Semaphorin3A, indicating that this extrinsic cue does not exert major effects at the level of nuclear transcription. We also compared our data to several published studies of DRG and SCG gene expression in animal models of regeneration, and found the expression of a large number of genes in common between neurite outgrowth in vitro and regeneration in vivo.ConclusionMany gene expression changes undergone by SCG and DRG during in vitro outgrowth are shared between these two tissue types and in common with in vivo regeneration models. This suggests that the genes identified in this in vitro study may represent new candidates worthy of further study for potential roles in the therapeutic regrowth of neuronal connections.
Highlights
The ability of a neuron to regenerate functional connections after injury is influenced by both its intrinsic state and by extrinsic cues in its surroundings
That the intrinsic state of a neuron can be manipulated to improve regeneration has been well-demonstrated in dorsal root ganglia (DRG) neurons, where neurite outgrowth in response to spinal nerve injury is significantly improved by a preceding peripheral nerve lesion [2,3,4,5]
In order to avoid focusing on transcripts unique to one tissue type versus another, we used a comparative strategy to look for effects that were common to two tissue types and more likely to be involved in the general process of neurite outgrowth
Summary
The ability of a neuron to regenerate functional connections after injury is influenced by both its intrinsic state and by extrinsic cues in its surroundings. That the intrinsic state of a neuron can be manipulated to improve regeneration has been well-demonstrated in dorsal root ganglia (DRG) neurons, where neurite outgrowth in response to spinal nerve injury is significantly improved by a preceding peripheral nerve lesion [2,3,4,5] This ability of intrinsic changes to influence neurite outgrowth has been further demonstrated by transgenic expression of genes such as cytoskeleton-associated protein 23 (CAP23), growth associated protein 43 (GAP43), small proline-rich repeat protein 1A (Sprr1A), and activating transcription factor 3 (Atf3) [6,7,8,9,10]. Grafts of peripheral nervous system (PNS) tissue at sites of central nervous system (CNS) lesion can improve neurite growth across an otherwise inhibitory scar, and much research has been focused on distinguishing the growth-permissive and growthinhibitory aspects of these two [16,17,18]
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