title: MET signaling in GABAergic neuronal precursors of the medial ganglionic eminence restricts GDNF activity in cells that express GFRα1 and a new transmembrane receptor partner.
abstract: GDNF (glial cell line-derived neurotrophic factor) promotes the differentiation and migration of GABAergic neuronal precursors of the medial ganglionic eminence (MGE). These functions are dependent on the GPI-anchored receptor GFRα1, but independent of its two known transmembrane receptor partners RET and NCAM. Here we show that soluble GFRα1 is also able to promote differentiation and migration of GABAergic MGE neurons. These activities require endogenous production of GDNF. Although GDNF responsiveness is abolished in Gfra1(-/-) neurons, it can be restored upon addition of soluble GFRα1, a result that is only compatible with the existence of a previously unknown transmembrane signaling partner for the GDNF-GFRα1 complex in GABAergic neurons. The roles of two candidate transmembrane receptors previously implicated in GABAergic interneuron development--MET, a receptor for hepatocyte growth factor (HGF), and ErbB4, the neuregulin receptor--were examined. GDNF did not induce the activation of either receptor, nor did inhibition of MET or ErbB4 impair GDNF activity in GABAergic MGE neurons. Unexpectedly, however, inhibition of MET or HGF per se promoted neuronal differentiation and migration and enhanced the activity of GDNF on MGE neurons. These effects were dependent on endogenous GDNF and GFRα1, suggesting that MET signaling negatively regulates GDNF activity in the MGE. In agreement with this, Met mutant MGE neurons showed enhanced responses to GDNF and inhibition of MET or HGF increased Gfra1 mRNA expression in MGE cells. In vivo, expression of MET and GFRα1 overlapped in the MGE, and a loss-of-function mutation in Met increased Gfra1 expression in this region. Together, these observations demonstrate the existence of a novel transmembrane receptor partner for the GDNF-GFRα1 complex and uncover an unexpected interplay between GDNF-GFRα1 and HGF-MET signaling in the early diversification of cortical GABAergic interneuron subtypes.
authors.affiliation: Department of Neuroscience, Karolinska Institute, S-171 77 Stockholm, Sweden.
authors.forename: Maurice
authors.initials: M
authors.lastname: Perrinjaquet
authors.forename: Dan
authors.initials: D
authors.lastname: Sjöstrand
authors.forename: Annalena
authors.initials: A
authors.lastname: Moliner
authors.forename: Sabrina
authors.initials: S
authors.lastname: Zechel
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lamballe
authors.forename: Flavio
authors.initials: F
authors.lastname: Maina
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Ibáñez
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002522:Chlorocebus aethiops; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005724:Ganglia / Q000473:pathology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000276:immunology / Q000378:metabolism*; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D008473:Median Eminence / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D019138:Antibodies, Blocking; C494988:Gfra1 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D007211:Indoles; D010879:Piperazines; D011799:Quinazolines; D013449:Sulfonamides; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D019859:Proto-Oncogene Proteins c-met; D066247:Receptor, ErbB-4