GDNF and neurturin are target-derived factors essential for cranial parasympathetic neuron development

During development, parasympathetic ciliary ganglion neurons arise from the neural crest and establish synaptic contacts on smooth and striate muscle in the eye. The factors that promote the ciliary ganglion pioneer axons to grow toward their targets have yet to be determined. Here, we show that gli al cell line-derived neurotrophic factor (GDNF) and neurturin (NRTN) consti tute target-derived factors for developing ciliary ganglion neurons. Both G DNF and NRTN are secreted from eye muscle located in the target and traject ory pathway of ciliary ganglion pioneer axons during the period of target i nnervation. After this period, however, the synthesis of GDNF declines mark edly, while that of NRTN is maintained throughout the cell death period. Fu rthermore, both in vitro and in vivo function-blocking of GDNF at early emb ryonic ages almost entirely suppresses ciliary axon outgrowth. These result s demonstrate that target-derived GDNF is necessary for ciliary ganglion ne urons to innervate ciliary muscle in the eye. Since the down-regulation of GDNF in the eye is accompanied by down-regulation of GFR alpha1 and Ret, bu t not of GFR alpha2, in innervating ciliary ganglion neurons, the results a lso suggest that target-derived GDNF regulates the expression of its high-a ffinity coreceptors.