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 glial cell line-derived neurotrophic factor (GDNF) and neurturin (NRTN) constitute target-derived factors for developing ciliary ganglion neurons. Both GDNF and NRTN are secreted from eye muscle located in the target and trajectory pathway of ciliary ganglion pioneer axons during the period of target innervation. After this period, however, the synthesis of GDNF declines markedly, while that of NRTN is maintained throughout the cell death period. Furthermore, both in vitro and in vivo function-blocking of GDNF at early embryonic ages almost entirely suppresses ciliary axon outgrowth. These results demonstrate that target-derived GDNF is necessary for ciliary ganglion neurons to innervate ciliary muscle in the eye. Since the down-regulation of GDNF in the eye is accompanied by down-regulation of GFRalpha1 and Ret, but not of GFRalpha2, in innervating ciliary ganglion neurons, the results also suggest that target-derived GDNF regulates the expression of its high-affinity coreceptors.
Hashino
E
E
Center for Hearing and Deafness, State University of New York at Buffalo, Buffalo, NY 14214, USA. hashino@acsu.buffalo.edu
Shero
M
M
Junghans
D
D
Rohrer
H
H
Milbrandt
J
J
Johnson
E M
EM
D000818:Animals; D002642:Chick Embryo; D020934:Ciliary Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D058966:Contactins; D015536:Down-Regulation; D029721:Drosophila Proteins; D005123:Eye / Q000196:embryology / Q000378:metabolism; D005726:Ganglia, Parasympathetic / Q000196:embryology* / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D051101:Neurturin; D010275:Parasympathetic Nervous System / Q000196:embryology* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020801:Receptor, Ciliary Neurotrophic Factor / Q000378:metabolism
D020934:Ciliary Neurotrophic Factor; D058966:Contactins; D029721:Drosophila Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules; D051101:Neurturin; D011518:Proto-Oncogene Proteins; D020801:Receptor, Ciliary Neurotrophic Factor; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila