Abstract：
:The NRG1 growth factor and ERBB4 receptor have been identified as leading schizophrenia risk genes. Although NRG1 and ERBB4 have been shown to modulate neuronal functions involved in schizophrenia, including both GABAergic and glutamatergic synapses, the exact molecular mechanisms remain poorly understood. Here we investigated ERBB4 intracellular domain, 4ICD, transactivator function in rat hippocampal cultures by inhibiting γ-secretase mediated ERBB4 regulated intramembrane proteolysis (RIP). NRG1 stimulation resulted in a dramatic increase in the number of hippocampal cells displaying nuclear 4ICD which was abolished in cultures pretreated with the γ-secretase inhibitor compound E (CE). To identify NRG1-4ICD transactivated genes we compared global gene expression profiles of hippocampal cultures stimulated with NRG1 in the absence or presence of CE. In concordance with the contribution of NRG1-ERBB4 signaling to dendritic spine maturation and schizophrenia, global gene expression analysis followed by Ingenuity Pathway Analysis of the dataset identified NRG1-4ICD regulated genes significantly represented in semaphorin signaling and actin cytoskeletal plasticity and multiple genes with confirmed roles in dendritic spine morphogenesis. Using the power of global gene expression analysis our data provides a proof-of-concept supporting a role for non-canonical NRG1-4ICD signaling in the regulation of gene expression contributing to normal and schizophrenic neuronal function.
journal_name
Neurosci Resjournal_title
Neuroscience researchauthors
Allison JG,Das PM,Ma J,Inglis FM,Jones FEdoi
10.1016/j.neures.2011.02.009subject
Has Abstractpub_date
2011-06-01 00:00:00pages
155-63issue
2eissn
0168-0102issn
1872-8111pii
S0168-0102(11)00051-4journal_volume
70pub_type
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