Adhesion-Controlled Mechanics of the Glial Niche Regulate Neural Stem Cell Proliferative Potential

ABSTRACT Controlled proliferation of neural stem cells (NSCs) builds a functional nervous system during development. While their cellular niche is recognized as a signalling hub, the contribution of its structure and mechanics in regulating neurogenesis remains unexplored. The Drosophila larval central nervous system contains self-renewing NSCs in close contact with cortex glial cells. Transcriptomics identified a triad of immunoglobulin superfamily cell adhesion molecules (Dpr10/Dpr6 in glia and DIP-α in NSCs) which physically and mechanically connect the NSC and glial membranes, acting as mechanoregulators. Their disruption increases glial cortical tension, causing non-autonomous mitotic defects in NSCs, characterized by abnormal spindle morphologies and impaired mitotic progression. Additionally, elevated glial tensile forces increase Lamin content in NSCs, a protective response also resulting in nuclear deformation. Ultimately NSC proliferative potential and genome integrity are compromised. Our study reveals that the native mechanical properties of the niche are transmitted to NSCs and regulate their function. Graphical abstract