Altering cell size asymmetry in Drosophila neural stem cells creates supernumerary stem cells with limited lineage expansion potential

Asymmetrically dividing invertebrate and vertebrate stem cells can generate unequal sized sibling cells. However, the functional implications of cell size asymmetry (CSA) are underexplored. Here, we use Drosophila neural stem cells (NSCs) to investigate how changes in CSA impact NSC proliferation and cell fate decisions. Using live cell imaging, NSC lineage analysis, and gene expression profiling, we find that altering CSA increases the NSC pool but decreases lineage size and the number of differentiating progeny cells. Modeling CSA in silico with a volume-sensitivity and NSC self-inhibition model can recapitulate these findings. Gene expression profiling further revealed that the NSC growth regulator Imp and the G1-S cell cycle regulator CycE are upregulated in NSCs with altered CSA, providing a potential molecular link to the volume-sensitivity model. We propose that cell size and position regulate NSC proliferation and differential potential, impacting lineage progression and progeny cell differentiation in the developing Drosophila brain.