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Basement membranes (BMs) are specialized layers of extracellular matrix (ECM) mainly composed of Laminin, type IV Collagen, Perlecan and Nidogen/entactin (NDG). While the essential and evolutionary conserved functions of Laminin, Collagen and Perlecan are well documented inDrosophilaand other species, the proposed role of NDG as the major ECM linker molecule has been challenged by severalin vivostudies revealing that NDG is dispensable for viability and BM formation. Here, we report the characterization of the singleNdggene inDrosophila.EmbryonicNdgexpression differed from that of other BM components and was primarily observed in mesodermal tissues and the chordotonal organs, whereas NDG protein localized to all BMs. While loss of Laminin strongly affected BM-localization of NDG,Ndgnull mutants exhibited no overt changes in the distribution of BM core components. However, loss of NDG led to ultrastructural BM defects compromising barrier function and stabilityin vivo.AlthoughNdgmutants were viable, loss of NDG led to decreased fecundity in flies as well as impaired crawling behavior and reduced response to vibrational stimuli in larvae. Further morphological analysis revealed accompanying defects in the larval peripheral nervous system especially in the chordotonal organs and the neuromuscular junction (NMJ), whereNdggenetically interacted with theLeukocyte-antigen-related-like (Lar) receptorgene to regulate NMJ extension and synaptic differentiation. Taken together, our analysis suggests that NDG is not essential for BM assembly but mediates BM stability and ECM-dependent neural plasticity duringDrosophiladevelopment.Summary StatementIn this study we characterizeDrosophila Nidogen/Entactin (Ndg)mutants revealing that loss of Ndg impairs basement membrane (BM) stability and permeability as well as proper function of the nervous system.