The extracellular matrix (ECM) regulates cell migration and sculpts organ shape. AdamTS proteins are extracellular metalloproteases known to modify ECM proteins and promote cell migration, but demonstrated roles for AdamTS proteins in regulating CNS structure and ensuring cell lineages remain fixed in place have not been uncovered. Using forward genetic approaches in Drosophila, we find that reduction of AdamTS-A function induces both the mass exodus of neural lineages out of the CNS and drastic perturbations to CNS structure. Expressed and active in surface glia, AdamTS-A acts in parallel to perlecan and in opposition to viking/collagen IV and βPSintegrin to keep CNS lineages rooted in place and to preserve the structural integrity of the CNS. viking/collagen IV and βPS-integrin are known to promote tissue stiffness and oppose the function of perlecan, which reduces tissue stiffness. Our work supports a model in which AdamTS-A anchors cells in place and preserves CNS architecture by reducing tissue stiffness. © 2017. Published by The Company of Biologists Ltd.