Neurogenomics of the Sympathetic Neurotransmitter Switch Indicates That Different Mechanisms Steer Cholinergic Differentiation in Rat and Chicken Models
Vertebrate sympathetic neurons have the remarkable potential to switch their neurotransmitter phenotype from noradrenergic to cholinergic—a phenomenon that has been intensively studied in rat and chicken models. In both species, loss of noradrenergic markers and concomitant upregulation of cholinergic markers occurs in response to neuropoietic cytokines such as ciliary neurotrophic factor (CNTF). However, other aspects of the neurotransmitter switch including developmental timing, target tissues of cholinergic neurons, and dependence on neurotrophic factors differ between the two species. Here we compare CNTF-triggered transcriptome changes in both species by using DNA microarrays. CNTF induced changes in 1130 out of 16084 analyzed genomic loci in rat sympathetic neurons. When this set of genes was compared to CNTF-induced changes in the chicken transcriptome, a surprisingly small overlap was found—only 94 genes were regulated in the same direction in chicken and rat. The differential responses of the transcriptome to neuropoietic cytokines provide additional evidence that the cholinergic switch, although conserved during vertebrate evolution, is a heterogeneous phenomenon and may result from differential cellular mechanisms. 1. Introduction Transmitter phenotypes are specified at defined stages during neuronal development through coordinated expression of complex sets of gene products, involved in the synthesis and transport of transmitters [1]. Once specified, the neurotransmitter phenotype remains permanently unaltered for most cell types. Rodent sympathetic neurons are a notable exception since they can transdifferentiate from a fully functional noradrenergic to a cholinergic phenotype in vitro and in vivo [2, 3]. This neurotransmitter switch serves as a textbook example of plasticity in postmitotic neurons and depends on growth factor signalling [4, 5]. The first identified cholinergic differentiation factors are ligands of the gp130/LIFRβ receptor complex and belong to the family of neuropoietic cytokines [6]. In vivo gp130/LIFRβ ligands are secreted from the target structure of cholinergic sympathetic neurons such as eccrine sweat glands [7]. In vitro, the sympathetic superior cervical ganglion (SCG) neurons dissected from postnatal rats represent the best studied model for cholinergic sympathetic development. These noradrenergic cells, upon exposure to neuropoietic cytokines such as ciliary neurotrophic factor (CNTF) or leukaemia inhibitory factor (LIF), downregulate markers for the noradrenalin synthesis including the tyrosine hydroxylase (Th)
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