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 the 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 is that subpopulations of motor neurons based on their function and/or their myotopic organization require distinct members of GDNF family ligands. Because responsiveness to the different ligands depends on the expression of their 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 furthermore examined the in vivo role of GDNF for cranial motor neuron subpopulations. The shared ret receptor was expressed in all somatic, branchial and visceral cranial embryonic motor nuclei examined, showing that they are all competent to respond to GDNF family ligands during development. At early stages of development both the GDNF receptor, gfralpha1, and the neurturin (NTN) receptor, gfralpha2, were expressed in the oculomotor, facial and spinal accessory, and only gfralpha1 in the trochlear, superior salivatory, trigeminal, hypoglossal and weakly in the dorsal motor nucleus of the vagus and the ambiguous nucleus. The abducens nucleus was negative for both gfralpha1 and gfralpha2. The artemin (ART) receptor, gfralpha3, was expressed only in the superior salivatory nucleus. A motor neuron subnuclei-specific expression of gfralpha1 and gfralpha2 was seen in the facial and trigeminal nuclei which corresponded to their dependence on GDNF in null mutant 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 attainment of changes in dependency could be ligand induced. Our results indicate that specific GDNF family ligands support selective muscle-motor neuron circuits during development.
Mikaels
A
A
Laboratory of Molecular Neurobiology, MBB, Karolinska Institute, S171 77 Stockholm, Sweden.
Livet
J
J
Westphal
H
H
De Lapeyrière
O
O
Ernfors
P
P
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001933:Brain Stem / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D003391:Cranial Nerves / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D029721:Drosophila Proteins; D005154:Facial Nerve / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D006579:Heterozygote; D017403:In Situ Hybridization; D008024:Ligands; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009046:Motor Neurons / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D005810:Multigene Family; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000145:classification / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000145:classification / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000145:classification / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017475:Receptors, Nerve Growth Factor; D014276:Trigeminal Nerve / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D014278:Trigeminal Nuclei / Q000166:cytology / Q000196:embryology / Q000378:metabolism
D018076:DNA, Complementary; D029721:Drosophila Proteins; C495040:Gdnf protein, mouse; C494988:Gfra1 protein, mouse; C494991:Gfra2 protein, mouse; C494994:Gfra3 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D008024:Ligands; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D017475:Receptors, Nerve Growth Factor; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C494999:Ret protein, mouse