Diversification of Dentate Gyrus Granule Cell Subtypes is Regulated by Neuregulin1 Nuclear Back Signaling

Neuronal heterogeneity is a defining feature of the developing mammalian brain, but the mechanisms regulating the diversification of closely related cell types remain elusive. In this study, we investigated the heterogeneity of dentate gyrus (DG) granule cells (GCs) and the influence of a psychosis associated V ₃₂₁ L mutation in Neuregulin1 (Nrg1) on GC subtype composition. Using morpho-electric characterization, single-nucleus gene expression, and chromatin accessibility profiling, we identified distinct morphological and molecular features of typical GCs and a rare subtype known as semilunar granule cells (SGCs). The V ₃₂₁ L mutation disrupts Nrg1 nuclear back-signaling, resulting in an overabundance of SGC-like cells. We discovered pseudotime gene expression trajectories suggesting the potential for GC-to-SGC transitions, supported by the accessibility of SGC-specific genes in other GCs. Intriguingly, we found an increase in SGC-marker expression over the adolescence to adulthood transition window in wild-type mice, coinciding with a decline in Nrg1 nuclear back-signaling capacity. This suggests that intact Nrg1 signaling suppresses SGC-like fate acquisition, and that its natural downregulation may underlie the emergence of SGC-like cells during postnatal development. Similarly, a pathological block of nuclear back signaling by the V ₃₂₁ L mutation in Nrg1, may result in acquisition of the SGC-like fate due to loss of the repressive mechanisms maintained by intact nuclear back signaling. Our findings reveal a novel role for Nrg1 in maintaining DG cell-type composition and suggest that disrupted subtype regulation may contribute to disease-associated changes in DG GC morphology and function. Understanding these mechanisms provides new insights into mechanisms of cell-type diversity and its potential role in psychiatric pathology.