GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE337nnn/GSE337485/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE337485GEOGSEfalseRAI1 safeguards fidelity and tempo of human neurodevelopmental gene expressionHuman brain development proceeds on an unusually long timeline, fostering the species' cognitive advantages. Retinoic Acid Induced 1 (RAI1) gene encodes a nucleosome-binding protein haploinsufficient in Smith–Magenis Syndrome (SMS), a neurodevelopmental disorder characterized by cognitive deficits with autistic features. However, the role of RAI1 in human neurodevelopment remains unexplored experimentally. Here, we generated isogenic heterozygous and homozygous RAI1 loss-of-function human embryonic stem cell lines and interrogated the roles of RAI1 in neurodevelopmental gene regulation. A longitudinal transcriptome study during in vitro cortical development revealed that RAI1 deficiency accelerates developmental transcriptome progression, as indicated by the induction of synaptic genes. Single-cell RNA-seq analysis revealed that RAI1-deficient neuroprogenitors acquire a transient mesoderm-like gene expression signature followed by pro-neuronal maturation gene expression in postmitotic neurons. Unexpectedly, the developmental acceleration signature was exacerbated during NGN2-induced excitatory neuron differentiation, suggesting functional interplay between RAI1 and NGN2-driven programs. Together, these results identify RAI1 as a suppressor of the mesodermal lineage program and as a novel brake that slows the tempo of human neurodevelopmental gene expression.2026/07/08GSE337485GSM9856239GSM9856238GSM9856259GSM9856237GSM9856258GSM9856236GSM9856235GSM9856257GSM9856278GSM9856256GSM9856234GSM9856255GSM9856233GSM9856277GSM9856232GSM9856276GSM9856254GSM9856275GSM9856253GSM9856231GSM9856252GSM9856274GSM9856273GSM9856251GSM9856272GSM9856250GSM9856271GSM9856270GSM9856249GSM9856248GSM9856269GSM9856247GSM9856246GSM9856268GSM9856267GSM9856245GSM9856266GSM9856244GSM9856265GSM9856243GSM9856264GSM9856242GSM9856241GSM9856263GSM9856240GSM9856262GSM9856261GSM985626024676337485Homo sapiens