Intramembranous valine linked to schizophrenia is required for neuregulin 1 regulation of the morphological development of cortical neurons.

Neuregulin 1 (NRG1) signaling is critical to various aspects of neuronal development and function. Among different NRG1 isoforms, the type III isoforms of NRG1 are unique in their ability to signal via the intracellular domain after gamma-secretase-dependent intramembranous processing. However, the functional consequences of type III NRG1 signaling via its intracellular domain are mostly unknown. In this study, we have identified mutations within type III NRG1 that disrupt intramembranous proteolytic processing and abolish intracellular domain signaling. In particular, substitutions at valine 321, previously linked to schizophrenia risks, result in NRG1 proteins that fail to undergo gamma-secretase-mediated nuclear localization and transcriptional activation. Using processing-defective mutants of type III NRG1, we demonstrate that the intracellular domain signaling is specifically required for NRG1 regulation of the growth and branching of cortical dendrites but not axons. Consistent with the role of type III NRG1 signaling via the intracellular domain in the initial patterning of cortical dendrites, our findings from pharmacological and genetic studies indicate that type III NRG1 functions in dendritic development independent of ERBB kinase activity. Together, these results support the proposal that aberrant intramembranous processing and defective signaling via the intracellular domain of type III NRG1 impair a subset of NRG1 functions in cortical development and contribute to abnormal neuroconnectivity implicated in schizophrenia.