GDNF is a chemoattractant for enteric neural cells

In situ hybridization revealed that GDNF mRNA in the mid- and hindgut mesen chyme of embryonic mice was minimal at E10.5 but was rapidly elevated at al l gut regions after Ell, but with a slight delay (0.5 days) in the hindgut. GDNF mRNA expression was minimal in the mesentery and in the pharyngeal an d pelvic mesenchyme adjacent to the gut. To examine the effect of GDNF on e nteric neural crest-derived cells, segments of E11.5 mouse hindgut containi ng crest-derived cells only at the rostral ends were attached to filter pap er supports and grown in catenary organ culture. With GDNF (100 ng/ml) in t he culture medium, threefold fewer neurons developed in the gut explants an d fivefold more neurons were present on the filter paper outside the gut ex plants, compared to controls. Thus, in: controls, crest-derived cells colon ized the entire explant and differentiated into neurons, whereas in the pre sence of exogenous GDNF, most crest-derived cells migrated out of the gut e xplant. This is consistent with GDNF acting as a chemoattractant. To test t his idea, explants of esophagus, midgut, superior cervical ganglia, paraver tebral sympathetic chain ganglia, or dorsal root ganglia from E11.5-E12.5 m ice were grown on collagen gels with a GDNF-impregnated agarose bead on one side and a control bead on the opposite side. Migrating neural cells and n eurites from the esophagus and midgut accumulated around the GDNF-impregnat ed beads, but neural cells in other tissues showed little or no chemotactic response to GDNF, although all showed GDNF-receptor (Ret and GFR alpha1) i mmunoreactivity. We conclude that GDNF may promote the migration of crest c ells throughout the gastrointestinal tract, prevent them from straying out of the gut (into the mesentery and pharyngeal and pelvic tissues), and prom ote directed axon outgrowth. (C) 2001 Academic Press.