A dynamic regulation of GDNF-family receptors correlates with a specific trophic dependency of cranial motor neuron subpopulations during development

Glial cell line-derived neurotrophic factor (GDNF) family ligands promote t he survival of developing motor neurons in vivo and in vitro. However, not all neurons survive with any single ligand in culture and GDNF null mutant mice display only a partial motor neuron loss. An interesting possibility i s that subpopulations of motor neurons based on their function and/or their myotopic organization require distinct members of GDNF family ligands. Bec ause responsiveness to the different ligands depends on the expression of t heir cognate ligand-binding receptor we have herein addressed this issue by examining the expression of GDNF-family receptors (gfr) during development and in the adult in cranial motor nuclei subpopulations. We have furthermo re examined the in vivo role of GDNF for cranial motor neuron subpopulation s. The shared ret receptor was expressed in all somatic, branchial and visc eral cranial embryonic motor nuclei examined, showing that they are all com petent to respond to GDNF family ligands during development. At early stage s of development both the GDNF receptor, gfr alpha 1, and the neurturin (NT N) receptor, gfr alpha 2, were expressed in the oculomotor, facial and spin al accessory, and only gfr alpha 1 in the trochlear, superior salivatory, t rigeminal, hypoglossal and weakly in the dorsal motor nucleus of the vagus and the ambiguus nucleus. The abducens nucleus was negative for both gfr al pha 1 and gfr alpha 2. The artemin (ART) receptor, gfr alpha 3, was express ed only in the superior salivatory nucleus. A motor neuron subnuclei-specif ic expression of gfr alpha 1 and gfr alpha 2 was seen in the facial and tri geminal nuclei which corresponded to their dependence on GDNF in null mutan t mice. We found that the expression was dynamic in these nuclei, which may reflect developmental changes in their trophic factor dependency. Analysis of GDNF null mutant mice revealed that the dynamic receptor expression is regulated by the ligand in vivo, indicating that the acquirement of changes in dependency could be ligand induced. Our results indicate that specific GDNF family ligands support selective muscle-motor neuron circuits during d evelopment.