Psychosis-associated Valine to Leucine mutation in Neuregulin1 disrupts expression of a schizophrenia susceptibility gene network within the hippocampus and alters adult hippocampal neurogenesis

Abstract

AbstractSchizophrenia is a complex genetic neurodevelopmental disorder. Expression quantitative trait loci (eQTLs) form the bulk of the genetic variation contributing to schizophrenia. Currently little is known about how eQTL expression is regulated or how this leads to the underlying cellular pathology. Neuregulin1-ErbB4 signaling plays a crucial role in synaptogenesis and has been implicated in schizophrenia. A psychosis-associated missense mutation in NRG1 (rs74942016) is predicted to impair Nrg1 nuclear back-signaling, which is involved in transcriptional regulation and dendritogenesis, thereby implicating this mode of signaling in the underlying cellular pathology. We generated a transgenic mouse harboring the rs74942016 mutation in nrg1. We investigated the effect of this mutation (V321L in Type III Nrg1) on Nrg1 nuclear signaling. We performed transcriptomic analysis of the mutant dentate gyrus (DG) and identified several developmental processes predicted to be altered compared to wildtype DG. We assessed neurogenesis, cell cycle dynamics, fate commitment, and neuronal maturation in vivo in the mutant neurogenic niche. We found that the V321L mutation impairs nuclear translocation of the Nrg1 ICD. RNA sequencing identified cell cycle regulation, differentiation, neurogenesis, and dendritic growth as dysregulated processes in the mutant DG. We experimentally confirmed these predictions. Key nodes along the neurogenesis developmental timeline were found to be disrupted in the mutant DG, resulting in abnormal dendrite morphology and neural fate specification. We found that orthologs of known schizophrenia susceptibility genes were dysregulated in the mutant DG and interacted within a larger network of dysregulated genes in the mutant DG. Importantly, the schizophrenia-associated genes functioned as hubs coordinating this larger network, and the additional nodes within this extended network were functionally linked to known physiological processes and pathways associated with schizophrenia. Thus, our data show that Nrg1 nuclear back signaling is an important regulator of cell proliferation, neuronal specification, and maturation in the adult mouse DG. Loss of Nrg1 nuclear back-signaling due to the V321L mutation disrupts adult neurogenesis and results in dysregulation of a schizophrenia susceptibility gene network.