Opposing functions of GDNF and NGF in the development of cholinergic and noradrenergic sympathetic neurons

We identified a population of mature sympathetic neurons in which Ret, the receptor for glial cell line-derived neurotrophic factor (GDNF), is coexpressed with the neurotrophin-3 (NT3) receptor TrkC and choline acetyltransferase. In a complementary population the nerve growth factor receptor TrkA is coexpressed with the norepinephrine transporter. In accordance with these in vivo results, GDNF and neurturin promote the expression of cholinergic marker genes in sympathetic chain explants, similar to NT3 and ciliary neuronotrophic factor (CNTF). To define intracellular signaling mechanisms commonly activated by NT3, GDNF, or CNTF to promote cholinergic differentiation, we have analyzed the activation of intracellular signaling cascades. Signal transducer and activator of transcription-3 (STAT3) was strongly activated by CNTF but not by GDNF or NT3 and hence is not essential for cholinergic differentiation. We conclude that cholinergic properties can be regulated by neurotrophic factors from three different protein families, whereas noradrenergic properties are promoted by NGF.