biostudies-literatureRajebhosale PNational Institute of Neurological Disorders and StrokeHHS | NIH | National Institute of Neurological Disorders and Strokee202403169https://www.ebi.ac.uk/biostudies/studies/S-EPMC12032840biostudies-literatureUnknown8(7)Neuronal heterogeneity is a defining feature of the developing mammalian brain, but the mechanisms regulating the diversification of closely related cell types remain elusive. Here, we investigated granule cell (GC) subtype composition in the dentate gyrus (DG) and the influence of a psychosis-associated V₃₂₁L mutation in Neuregulin1 (Nrg1). Using morphoelectric characterization, single-nucleus gene expression, and chromatin accessibility profiling, we identified distinctions between typical GCs and a rare subtype known as semilunar granule cells (SGCs). We found that the V₃₂₁L mutation, which disrupts Nrg1 nuclear back-signaling, results in overabundance of SGC-like cells. Pseudotime analyses suggest a GC-to-SGC transition potential, supported by the accessibility ofLife science allianceDiversification of dentate gyrus granule cell subtypes is regulated by Nrg1 nuclear back-signaling.PMC12032840ZIANS009424ZIANS009416Ressa HJTalmage DADesai NSJiang LJohnson KRJone ARajebhosale PRole LWfalseDiversification of dentate gyrus granule cell subtypes is regulated by Nrg1 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. Here, we investigated granule cell (GC) subtype composition in the dentate gyrus (DG) and the influence of a psychosis-associated V₃₂₁L mutation in Neuregulin1 (Nrg1). Using morphoelectric characterization, single-nucleus gene expression, and chromatin accessibility profiling, we identified distinctions between typical GCs and a rare subtype known as semilunar granule cells (SGCs). We found that the V₃₂₁L mutation, which disrupts Nrg1 nuclear back-signaling, results in overabundance of SGC-like cells. Pseudotime analyses suggest a GC-to-SGC transition potential, supported by the accessibility of2025-01-01T00:00:00Z2025 Jul2025-07-03T03:04:43.112Z2025-07-03T03:04:43.112ZS-EPMC120328404028071310.26508/lsa.202403169