Abstract
Cell-type specific intrinsic programs instruct neuronal subpopulations before target-derived factors influence later neuronal maturation. Retrograde neurotrophin signaling controls neuronal survival and maturation of dorsal root ganglion (DRG) sensory neurons, but how these potent signaling pathways intersect with transcriptional programs established at earlier developmental stages remains poorly understood. Here we determine the consequences of genetic alternation of NT3 signaling on genome-wide transcription programs in proprioceptors, an important sensory neuron subpopulation involved in motor reflex behavior. We find that the expression of many proprioceptor-enriched genes is dramatically altered by genetic NT3 elimination, independent of survival-related activities. Combinatorial analysis of gene expression profiles with proprioceptors isolated from mice expressing surplus muscular NT3 identifies an anticorrelated gene set with transcriptional levels scaled in opposite directions. Voluntary running experiments in adult mice further demonstrate the maintenance of transcriptional adjustability of genes expressed by DRG neurons, pointing to life-long gene expression plasticity in sensory neurons.
Highlights
The assembly of neuronal circuits represents a sequential process during which neuronal subpopulations are first specified by cell-intrinsic programs at early developmental stages [1,2,3,4,5], before neuronal differentiation is further influenced by target-derived signals [6,7]
The expression of the Runt domain transcription factor Runx3 is highly restricted to proprioceptive Dorsal root ganglia (DRG) neurons [29,30], prompting us to determine the overlap between Runx3 and green fluorescent protein (GFP) expression in TrkCGFP transgenic mice
We found that in p0 lumbar DRG, .95% of GFPon DRG neurons co-express Runx3, and most Runx3on neurons are associated with GFP expression (Fig. 1a, b)
Summary
The assembly of neuronal circuits represents a sequential process during which neuronal subpopulations are first specified by cell-intrinsic programs at early developmental stages [1,2,3,4,5], before neuronal differentiation is further influenced by target-derived signals [6,7]. Intrinsic cell type specific differences are reflected at the gene expression level, and neuronal subtypes express unique genes controlling initial axon guidance decisions. Little is known about how profoundly target-derived signals influence these initial transcriptional profiles at the genome-wide level in neuronal subpopulations. Cell-type specific differences at the gene expression level include transcription factors and transmembrane receptors [1], with neurotrophic factor receptors and their ligands as one of the best-understood signaling systems [10,11,12]. Distinct DRG populations express the tyrosine kinase receptors TrkA and TrkC, and the targetderived factors nerve growth factor (NGF) and Neurotrophin-3 (NT3) regulate differential neuronal survival [10,11,12,13,14]. Since proprioceptors are a minority of DRG neurons [18,19], it remains unknown how they respond more generally to retrograde NT3 signaling by adjusting gene expression [14], and whether variation in NT3 level can modulate transcription within proprioceptors
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