Neural-specific UBAP2L deficiency causes developmental delay and cortical abnormalities in mice

Abstract

Rare UBAP2L variants have been linked to neurodevelopmental disorders (NDDs), such as autism spectrum disorder (ASD), but the role of UBAP2L in brain development remains unclear. Here, we generated neural-specific conditional knockout mice for Ubap2l using Nestin-Cre system, including heterozygous (cHET) and homozygous (cKO) mutants, to investigate the role of UBAP2L in neurodevelopment. Histological analyses revealed that adult cKO mice exhibited reduced body weight and fewer mature cortical neurons. At embryonic day 18.5 (E18.5), these mutant mice showed abnormal cortical lamination. Additionally, at E14.5, the abundance of cortical neural progenitor cells was reduced, and their proliferation was impaired. Ubap2l cKO mice exhibited impaired social interaction and deficits in learning and memory, whereas cHET mice showed milder behavioral and cognitive impairments. Transcriptomic profiling of the E14.5 cortex showed that differentially expressed genes were enriched in transcriptional regulation, neuronal differentiation, and cell proliferation, with proliferation-related genes predominantly downregulated. Pathway analysis further revealed dysregulation of the PI3K-AKT, MAPK, and Wnt signaling pathways. Cell-cycle analysis in the E14.5 cortex, together with flow cytometric analysis of UBAP2L-deficient cells, demonstrated that Ubap2l loss causes cell-cycle defects, namely S-phase shortening and G2/M arrest. Re-expression of wild-type UBAP2L rescued these defects, whereas NDD-associated UBAP2L variants failed to rescue cell-cycle progression. Collectively, these findings indicate that UBAP2L is required for cortical development and that its deficiency contributes to ASD-related phenotypes by disrupting neural progenitor proliferation and cell-cycle progression.