Organs are characterized by a specific shape that is often remodeled during development. The dynamics of organ shape is in particular evident during the formation of the Drosophila nervous system. During embryonic stages the central nervous system compacts, whereas selective growth occurs during larval stages. The nervous system is covered by a layer of surface glial cells that form the blood brain barrier and a thick extracellular matrix called neural lamella. The size of the neural lamella is dynamically adjusted to the growing nervous system and we show here that perineurial glial cells secrete proteases to remodel this matrix. Moreover, an imbalance in proteolytic activity results in an abnormal shape of the nervous system. To identify further components controlling nervous system shape we performed an RNAi based screen and identified the gene nolo, which encodes an ADAMTS-like protein. We generated loss of function alleles and demonstrate a requirement in glial cells. Mutant nolo larvae, however, do not show an abnormal nervous system shape. The only predicted off-target of the nolo(dsRNA) is Oatp30B, which encodes an organic anion transporting protein characterized by an extracellular protease inhibitor domain. Loss of function mutants were generated and double mutant analyses demonstrate a genetic interaction between nolo and Oatp30B which prevented the generation of maternal zygotic mutant larvae.