RAI1 safeguards fidelity and tempo of human neurodevelopmental gene expression
Year: 2026
Type: preprint
Abstract: Human brain development proceeds on an unusually long timeline relative to other species, a feature that is thought to foster advanced cognitive abilities. The Retinoic Acid Induced 1 (RAI1) gene encodes a nucleosome-binding protein, and its haploinsufficiency is responsible for Smith–Magenis Syndrome (SMS), a neurodevelopmental disorder characterized by cognitive impairment 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 analysis during in vitro cortical development revealed that RAI1 deficiency accelerates the progression of developmental gene expression. Single-cell RNA-seq analysis revealed that RAI1- deficient neuroprogenitors acquire a transient mesoderm-like gene expression signature, followed by a pro-neuronal maturation signature in postmitotic neurons. Unexpectedly, the developmental acceleration signature was exacerbated during NGN2-induced excitatory neuron differentiation, isolating the roles of RAI1 in neuronal differentiation from non-neuronal functions. Together, these results identify RAI1 as a suppressor of the mesodermal lineage program and as a brake that slows the tempo of human neurodevelopmental gene expression.
Institutions: University of Michigan, Michigan Medicine, Meikai University
Language: English
Subfield: Developmental Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: Diurnal Experimental Models to Investigate Neural Mechanisms of Sleep Disturbance in Smith-Magenis Syndrome, Developing a Diurnal Rodent Model for Smith-Magenis Syndrome, University of Michigan Rogel Cancer Center Support Grant 2023-2028, Circadian and homeostatic regulation of sleep in a diurnal model of Smith-Magenis Syndrome, Dissecting Histone H3K4 Methylation Enzymes in Neuroplasticity
OpenAlex ID: W7164584734