title: RET PLCγ phosphotyrosine binding domain regulates Ca2+ signaling and neocortical neuronal migration.
abstract: The receptor tyrosine kinase RET plays an essential role during embryogenesis in regulating cell proliferation, differentiation, and migration. Upon glial cell line-derived neurotrophic factor (GDNF) stimulation, RET can trigger multiple intracellular signaling pathways that in concert activate various downstream effectors. Here we report that the RET receptor induces calcium (Ca(2+)) signaling and regulates neocortical neuronal progenitor migration through the Phospholipase-C gamma (PLCγ) binding domain Tyr1015. This signaling cascade releases Ca(2+) from the endoplasmic reticulum through the inositol 1,4,5-trisphosphate receptor and stimulates phosphorylation of ERK1/2 and CaMKII. A point mutation at Tyr1015 on RET or small interfering RNA gene silencing of PLCγ block the GDNF-induced signaling cascade. Delivery of the RET mutation to neuronal progenitors in the embryonic ventricular zone using in utero electroporation reveal that Tyr1015 is necessary for GDNF-stimulated migration of neurons to the cortical plate. These findings demonstrate a novel RET mediated signaling pathway that elevates cytosolic Ca(2+) and modulates neuronal migration in the developing neocortex through the PLCγ binding domain Tyr1015.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: T Kalle
authors.initials: TK
authors.lastname: Lundgren
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Nakahata
authors.forename: Nicolas
authors.initials: N
authors.lastname: Fritz
authors.forename: Paola
authors.initials: P
authors.lastname: Rebellato
authors.forename: Songbai
authors.initials: S
authors.lastname: Zhang
authors.forename: Per
authors.initials: P
authors.lastname: Uhlén
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D020013:Calcium Signaling / Q000502:physiology*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D019579:Neocortex / Q000196:embryology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D053496:Inositol 1,4,5-Trisphosphate Receptors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019000:Phosphotyrosine; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D051966:Phospholipase C gamma