Neuregulin1 alpha activates migration of neuronal progenitors expressing ErbB4

Deficits in neuronal migration during development in the central nervous system may contribute to psychiatric diseases. The ligand neuregulin1 (NRG1) and its receptor ErbB4 are genes conferring susceptibility to schizophrenia, playing a key role in the control of neuronal migration both during development and adulthood. Several NRG1 and ErbB4 isoforms were identified, which deeply differ in their characteristics. Here we focused on the four ErbB4 isoforms and the two NRG1 isoforms differing in their EGF-like domain, namely alpha and beta. We hypothesized that these isoforms, which are differently regulated in schizophrenic patients, could play different roles in neuronal migration. Our hypothesis was strengthened by the observation that both NRG1 alpha and NRGl beta and the four ErbB4 isoforms are expressed in the medial and lateral ganglionic eminences and in the cortex during development in rat. We analysed in vitro the signal transduction pathways activated by the different ErbB4 isoforms following the treatment with soluble recombinant NRGl alpha or NRG1 beta and the ability to stimulate migration. Our data show that two ErbB4 isoforms, namely JMa-cyt2 and JMb-cytl, following NRG1 alpha and NRG1 beta treatment, strongly activate AKT phosphorylation, conferring high migratory activity to neuronal progenitors, thus demonstrating that both NRG1 alpha and NRG1 beta can play a role in neuronal migration. (C) 2016 Elsevier Inc. All rights reserved.