Abstract
The sympathetic innervation of sweat glands undergoes a target-induced noradrenergic to cholinergic/peptidergic switch during development. Similar changes are induced in cultured sympathetic neurons by sweat gland cells or by one of the following cytokines: leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), or cardiotrophin-1 (CT-1). None of these is the sweat gland-derived differentiation activity. LIF, CNTF, and CT-1 act through the known receptors LIF receptor beta (LIFRbeta) and gp130 and well defined signaling pathways including receptor phosphorylation and STAT3 activation. Therefore, to determine whether the gland-derived differentiation activity was a member of the LIF/CNTF cytokine family, we tested whether it acted via these same receptors and signal cascades. Blockade of LIFRbeta inhibited the sweat gland differentiation activity in neuron/gland co-cultures, and extracts of gland-containing footpads stimulated tyrosine phosphorylation of LIFRbeta and gp130. An inhibitor (CGX) of molecules that bind the CNTFRalpha, which is required for CNTF signaling, did not affect the gland-derived differentiation activity. Soluble footpad extracts induced the same changes in NBFL neuroblastoma cells as LIF and CNTF, including increased vasoactive intestinal peptide mRNA, STAT3 dimerization, and DNA binding, and stimulation of transcription from the vasoactive intestinal peptide cytokine-responsive element. Thus, the sweat gland-derived differentiation activity uses the same signaling pathway as the neuropoietic cytokines, and is likely to be a family member.
Highlights
The sympathetic innervation of sweat glands undergoes a target-induced noradrenergic to cholinergic/peptidergic switch during development
Similar results were observed in sympathetic neurons treated with footpad extracts from wild type and ciliary neurotrophic factor (CNTF) Ϫ/Ϫ mice rather than co-cultured with sweat gland cells, indicating that inhibition of LIFR on neurons rather than gland cells was responsible for the lack of neuronal choline acetyltransferase (ChAT) induction
These results suggest that the sweat gland-derived differentiation factor acts through the LIFR to induce changes in sympathetic neuron phenotype
Summary
The sympathetic innervation of sweat glands undergoes a target-induced noradrenergic to cholinergic/peptidergic switch during development. Similar changes are induced in cultured sympathetic neurons by sweat gland cells or by one of the following cytokines: leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), or cardiotrophin-1 (CT-1). None of these is the sweat gland-derived differentiation activity. CNTF, LIF, and CT-1, members of a larger family of molecules known as the neuropoietic cytokines, are currently the only proteins known to produce the changes in sympathetic neuron phenotype in vitro that are observed during the development of the sweat gland innervation in vivo. LIF, CNTF, and CT-1 are the only currently identified proteins that produce all of the changes in sympathetic neuron phenotype induced by sweat glands, it is unlikely that any of them is responsible for the differentiation activity present in sweat glands
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