Sympathetic neurons can switch their neurotransmitter phenotype from noradrenergic to cholinergic on exposure to neuropoietic cytokines in vitro and in vivo. Here, we provide evidence that this transspecification is regulated by the chromatin architecture protein Satb2. Treatment with the neuropoietic cytokines ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor rapidly and strongly increases Satb2 transcript and protein levels in cultures of rat superior cervical ganglia neurons.

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Although the p38 mitogen-activated protein kinases are active in many neuronal populations in the peripheral and central nervous systems, little is known about the physiological functions of p38 in postmitotic neurons. We report that p38 activity determines in vitro and in vivo the switch from noradrenergic to cholinergic neurotransmission that occurs in sympathetic neurons on exposure to the neuropoietic cytokines CNTF and LIF. This transdifferentiation serves as a model for the plastic mechanisms that enable mature neurons to change some of their central functions without passing through the cell cycle. We demonstrate that in postmitotic neurons, p38 and STAT pathways are concurrently activated by neuropoietic cytokine treatment for at least 12 h overlapping with changes in neurotransmitter marker gene expression. Inhibition of p38 blocks the upregulation of the nuclear matrix protein Satb2 and of cholinergic markers by CNTF without affecting STAT3 phosphorylation. Conversely, overexpression of p38␣ or ␤ in the absence of cytokines stimulates cholinergic marker expression. The neurotransmitter switch in vitro is impaired in neurons isolated from p38␤ Ϫ/Ϫ mice. Consistent with these in vitro results, a substantial loss of cells expressing cholinergic properties is observed in vivo in the stellate ganglion of mature mice deficient in the p38␤ isoform.

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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.