PROMOTION OF THE DEVELOPMENT OF ENTERIC NEURONS AND GLIA BY NEUROPOIETIC CYTOKINES - INTERACTIONS WITH NEUROTROPHIN-3

Neurotrophin-3 (NT-3) is known to promote enteric neuronal and glial d evelopment. Ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) were investigated to test the hypothesis that the develo pment of subsets of enteric neurons and/or glia is also affected by a neuropoietic cytokine, by itself, or together with NT-3. Crest-derived cells, immunoselected from the fetal rat gut (E14) with antibodies to p75(NTR), were found by RT-PCR and immunocytochemistry (after culture ) to express both alpha (CNTFR alpha) and beta components (gp130 and L LFR beta) of the tripartite CNTF receptor. In situ, myenteric ganglia below the esophagus were CNTFR alpha-immunoreactive by E16-E18. In vit ro, CNTF and LIP induced in crest-derived cells nuclear translocation of STAT3 (signal transducer and activator of transcription 3), a conce ntration-dependent increase in expression of neuronal or glial markers , and a decrease in expression of the precursor marker, nestin. LIFR b eta was expressed by more cells than CNTFR alpha; therefore, although the factors were equipotent, the maximal effect of LIF > CNTF. The cyt okines and NT-3 were additive in promoting neuronal but not glial deve lopment. Specifically, the development of neurons expressing NADPH-dia phorase activity (an early marker found in inhibitory motor neurons) w as promoted by CNTF and NT-3. These observations support the idea that a ligand for the tripartite CNTF receptor complex plays a role in ENS development. (C) 1998 Academic Press.