Integrator subunit IntS11 orchestrates the temporal dynamics of neural lineage progression in Drosophila

IntS11, the core catalytic subunit of the Integrator (INT), functions in various stages of transcription. However, its specific function in orchestrating neural lineage progression remains poorly understood.

Using a Drosophila model, we found that the absence of IntS11 leads to reduced brain size, which is not attributable to neuroblast (NB) loss or apoptosis but is due to impaired NB proliferation. MARCM (mosaic analysis with a repressible cell marker) revealed impaired clonal expansion, characterized by a significant decrease in progeny cell number. Live imaging and FUCCI analysis further confirmed a G1 arrest in IntS11-deficient NBs. Single-cell RNA-seq revealed downregulation of cell cycle regulators (aurB, CycE, Cdk4) in NBs and differentiation genes in GMCs, which were confirmed as candidates by ChIP-qPCR. Approximately 80% of neuronal morphogenesis-associated genes exhibiting 3'UTR shortening were downregulated. We further established that IntS11 physically binds to these loci to maintain lengthened 3'UTR isoforms and ensure mRNA stability in larval brains.

Collectively, our findings establish IntS11 as a stage-specific regulator of neural lineage progression that sustains NB proliferation through transcriptional control of cell-cycle genes and stabilizes differentiation programs by maintaining long 3'UTR isoforms.