Journal Article

RET PLCγ Phosphotyrosine Binding Domain Regulates Ca2+ Signaling and Neocortical Neuronal Migration

Uhlén, Per, Rebellato, Paola, Lundgren, T. Kalle, Nakahata, Katsutoshi, Fritz, Nicolas, Zhang, Songbai

2012

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Apoptosis / Binding / Biochemistry / Biology / Biophysics / Blotting, Western / Ca2+/calmodulin-dependent protein kinase II / Calcium / Calcium (reticular) / Calcium Signaling - physiology / Calcium signalling / Cell migration / Cell Movement / Cell Proliferation / Cells, Cultured / Dopamine / Electroporation / Embryo, Mammalian - cytology / Embryo, Mammalian - metabolism / Embryogenesis / Embryonic growth stage / Endoplasmic reticulum / Extracellular signal-regulated kinase / Gene silencing / Glial cell line-derived neurotrophic factor / Glial Cell Line-Derived Neurotrophic Factor - genetics / Glial Cell Line-Derived Neurotrophic Factor - metabolism / Humans / Immunoenzyme Techniques / Inositol 1,4,5-trisphosphate receptors / Inositol 1,4,5-Trisphosphate Receptors - genetics / Inositol 1,4,5-Trisphosphate Receptors - metabolism / Intracellular signalling / Kinases / Ligands / Mice / Mutation / Neocortex / Neocortex - embryology / Neocortex - metabolism / Nervous system / Neural stem cells / Neuronal-glial interactions / Neurons - cytology / Neurons - metabolism / Phospholipase / Phospholipase C gamma - antagonists & inhibitors / Phospholipase C gamma - genetics / Phospholipase C gamma - metabolism / Phosphorylation / Phosphotyrosine - metabolism / Point mutation / Proteins / Proto-Oncogene Proteins c-ret - genetics / Proto-Oncogene Proteins c-ret - metabolism / Real-Time Polymerase Chain Reaction / Ribonucleic acid / RNA / RNA, Messenger - genetics / RNA, Small Interfering - genetics / Signal transduction / Stem cells / Tyrosine / Ventricle