Abstract
Septate junctions (SJs) display a unique ultrastructural morphology with ladder-like electron densities that are conserved through evolution. Genetic and molecular analyses have identified a highly conserved core complex of SJ proteins consisting of three cell adhesion molecules Neurexin IV, Contactin, and Neuroglian, which interact with the cytoskeletal FERM domain protein Coracle. How these individual proteins interact to form the septal arrays that create the paracellular barrier is poorly understood. Here, we show that point mutations that map to specific domains of neurexin IV lead to formation of fewer septae and disorganization of SJs. Consistent with these observations, our in vivo domain deletion analyses identified the first Laminin G-EGF-Laminin G module in the extracellular region of Neurexin IV as necessary for the localization of and association with Contactin. Neurexin IV protein that is devoid of its cytoplasmic region is able to create septae, but fails to form a full complement of SJs. These data provide the first in vivo evidence that specific domains in Neurexin IV are required for protein-protein interactions and organization of SJs. Given the molecular conservation of SJ proteins across species, our studies may provide insights into how vertebrate axo-glial SJs are organized in myelinated axons.
Highlights
In Drosophila, the pleated septate junctions (SJs) form a barrier to the paracellular movement of ions and macromolecules that is conserved across species [1,2,3]
The primary structure of Neurexin IV (Nrx IV) is characterized by the presence of a signal peptide, a discoidin (Disc) domain, a laminin (Lam) G domain and two modules of laminin G-EGF-laminin G (LEL) in its extracellular region followed by a transmembrane (TM) and a short 48 amino acid cytoplasmic (CT) region (Fig. 1A) [12]
Cont localization and epithelial SJ organization, we characterized previously isolated nrx IV EMS alleles: nrx IV1817, nrx IV319, nrx IV711 and nrx IV2511 (Fig. 1), in addition to the more extensively studied nrx IV4304 null allele [8,12,13,14,36]. The mutations in these alleles are summarized in the schematic (Fig. 1A). nrx IV319 and nrx IV711 alleles carry missense mutations in two different laminin G domains (Fig. 1A, B)
Summary
In Drosophila, the pleated septate junctions (SJs) form a barrier to the paracellular movement of ions and macromolecules that is conserved across species [1,2,3]. Drosophila SJs and vertebrate axo-glial SJs consist of a core complex of three cell adhesion molecules These are Drosophila Neurexin IV (Nrx IV), Contactin (Cont) and Neuroglian (Nrg) and their vertebrate orthologs Caspr, Contactin and Neurofascin 155 [8,10,12,13]. Numerous other SJ proteins have been identified that are required for SJ formation These include the MAGUK proteins Discs large [19,20] and Varicose [21,22], the claudin-related proteins Sinuous [23], Megatrachea [24] and Kune-kune [25], the Na K-ATPase [26], the cell adhesion protein Lachesin [27] and a more recently discovered Ly6 family of GPI anchored proteins Boudin [28], Crooked, Crimpled and Coiled [29]. How these proteins are involved in the assembly of SJs is still not fully understood
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