Multiple actions of neurturin correlate with spatiotemporal patterns of ret expression in developing chick cranial ganglion neurons

The neurotrophic effects of neurturin (NRTN) on chick cranial ganglia were evaluated at various embryonic stages in vitro and related to its receptor expression. NRTN promoted the outgrowth and survival of ciliary ganglion ne urons at early embryonic (E) stages (E6-E12), trigeminal ganglion neurons a t mid-stages (E9-E16), and vestibular ganglion neurons at late stages (E12- E16). NRTN had no positive effects on cochlear ganglion neurons throughout development. In accordance with the time and order of onset in NRTN respons iveness, Ret protein was first detected in ciliary ganglia at E6, subsequen tly in trigeminal ganglia at E9, and in vestibular ganglia at E12. Ret was absent in E16 ciliary ganglia as well as in cochlear ganglia at all develop mental stages that were tested. Exogenous application of retinoic acid indu ced NRTN responsiveness and Ret protein expression from E9 vestibular gangl ion neurons, suggesting that retinoic acid can regulate Ret protein express ion in peripheral sensory neurons in vitro. Ret was confined to the neuron cell body, whereas GFR alpha was localized predominantly in peripheral and central neurite processes. No noticeable change in GFR alpha expression was seen in any cranial ganglia throughout the developmental stages that were tested (E6-E16). These results demonstrate that NRTN exerts neurotrophic ef fects on different cranial ganglia at different developmental stages and th at the onset and offset of NRTN responsiveness are regulated mainly by the spatiotemporal patterns of Ret, but not of GFR alpha receptors. The results also substantiate the recently emerging view that NRTN may be an essential target-derived neurotrophic factor for parasympathetic neurons during deve lopment.