InteractiveFly: GeneBrief

coiled: Biological Overview | References

The blood-brain barrier of Drosophila is established by the subperineurial glial cells that encase the CNS and PNS. The subperineurial glial cells are thin, highly interdigitated cells with epithelial character. The establishment of extensive septate junctions between these cells is crucial for the prevention of uncontrolled paracellular leakage of ions and solutes from the hemolymph into the nervous system. In the absence of septate junctions, macromolecules such as fluorescently labeled dextran can easily cross the blood-brain barrier. To identify additional components of the blood-brain barrier, a genetic approach was followed, and Texas-Red-conjugated dextran was injected into the hemolymph of embryos homozygous for chromosomal deficiencies. In this way, the 153-aa-large protein Coiled, a new member of the Ly6 (leukocyte antigen 6) family, was identified as being crucially required for septate junction formation and blood-brain barrier integrity. In coiled mutants, the normal distribution of septate junction markers such as NeurexinIV, Coracle, or Discs large is disturbed. EM analyses demonstrated that Coiled is required for the formation of septate junctions. It was further shown that Coiled is expressed by the subperineurial glial cells in which it is anchored to the cell membrane via a glycosylphosphatidylinositol anchor and mediates adhesive properties. Clonal rescue studies indicate that the presence of Coiled is required symmetrically on both cells engaged in septate junction formation (Syed, 2011).

The functionality of neuronal networks primarily depends on the precise regulation of ion concentrations in their environment. The nervous system therefore requires its efficient insulation from circulating blood or hemolymph systems. In consequence, in higher organisms, a blood-brain barrier (BBB) actively ensures a constant ionic environment needed for reliable neuronal function (Syed, 2011).

In invertebrates, the BBB is brought about by glial cells, and, despite many differences in the organization of the nervous system in invertebrates and vertebrates, many functional properties are evolutionary conserved. Drosophila provides a number of experimental advantages to study the BBB formation and function. A variety of glial subtypes have been identified in Drosophila, and many tools to visualize and manipulate them have been developed. The insect nervous system is surrounded by hemolymph with a high potassium concentration of ~50 mm. Perineurial and subperineurial glial (SPG) cells, which also express unidirectionally acting xenobiotic transporters, provide the cellular basis of the BBB. In particular, the extensively interdigitating subperineurial glial cells seal the nervous system by forming septate junctions, which mediate a tight cellular contact that prevents uncontrolled paracellular leakage of solutes from the hemolymph into the nervous system. Although the organization of septate junctions has been well characterized by EM analysis, almost nothing is known how this intricate structure develops and how its final barrier function is set up (Syed, 2011).

The notion that the molecular principles underlying glial differentiation are conserved between the mammalian and the Drosophila nervous system was also supported by recent work on the molecular components of septate junctions in Drosophila and septate-like junctions at the paranode of myelinating glia cells in vertebrates. Mutants lacking septate junctions between the subperineurial glia show paracellular leakage of potassium into the nervous system. Moreover, a reduction of septate junction length, as can be seen in Drosophila moody mutants, impairs BBB function. To further decipher the molecular components required for a functional BBB in Drosophila, a genetic screen was performed and the coiled gene, which encodes a small glycosylphosphatidylinositol (GPI)-linked protein of the Ly6 (leukocyte antigen 6)/CD59 family, was uncovered. Coiled is secreted to the cell surface, where it mediates cell adhesion. Clonal analysis demonstrates that Coiled is required in two neighboring cells to ensure the correct distribution of septate junction proteins (Syed, 2011).

The BBB is generated during late embryonic stages by the subperineurial glia. These cells remain in place until adult stages, and the septate junctions established remain stable over a very long time. Work on the tracheal system and the developing ectoderm has revealed a large number of genes required for the establishment of septate junctions. To date, ~18 cell-surface proteins have been described that are all structurally associated with septate junctions. Among these, some mediate homophilic adhesion, such as the GPI-linked protein Lachesin or the Ig-domain protein Fasciclin3, whereas other proteins mediate heterophilic adhesion, such as NeurexinIV or Gliotactin. Interestingly, septate junction organization appears identical in the CNS and other ectodermal derivatives, and, for many septate junction components, a disruption of the blood-brain barrier integrity has been demonstrated (Syed, 2011).

This study has shown that the Ly6 protein family member Coiled mediates homophilic adhesion and is also required for septate junction formation. In line with the morphological results, dye penetration kinetics were identified similar to mutants lacking the nrxIV gene, which is also crucially required for septate junction formation. A GFP–exon trap indicates that Coiled is specifically expressed in the subperineurial glia in which it is enriched in septate junctions. The GFP-tagged protein is not functional, and most of it appears to accumulate in the cytoplasm. In contrast, expression of an N-terminally HA-tagged Coiled variant, which is also nonfunctional, becomes secreted and diffuses in the nervous system. When a C-terminally tagged Coiled protein was expressed, the protein could not be easily detected in tissue but was detected in Western blots, suggesting that the C-terminally tagged Coiled protein is masked when integrated in septate junctions. A C-terminally tagged, truncated Coiled variant lacking the GPI anchor, which cannot rescue the mutant coiled phenotype, also appears to be weakly expressed. This indicates that the mutant protein is incorporated into the septate junctions, but as a result of the lack of its GPI anchor, it cannot mediate adhesive functions and is nonfunctional (Syed, 2011).

Coiled is a member of the Ly6 family characterized by a conserved set of 10 cysteine residues. The 3D structure of the Ly6/CD59 proteins has been resolved and resembles the one shown by certain snake neurotoxins, which target specific nicotinic acetylcholine receptors (Tsetlin, 1999; Huang, 2007). The CD59 protein, a small glycosylated protein, is linked to the plasma membrane via a GPI anchor. A prime function of CD59 is during complement activation, when it inhibits the assembly of the terminal membrane attack complex and thereby prevents damage to 'self' cells (Meri, 1990). Ly6 proteins are involved in early steps of T-cell-receptor-mediated T-cell activation (Kimberley, 2007). Recent studies provided evidence that Ly6-related proteins mediate cell adhesion and interact with unknown ligands on the antigen-presenting cells, which leads to T-cell suppression. Interestingly, the human E48 antigen, another member of the Ly6 family, is required in lymphocyte extravasation through the endothelium. Interactions of Ly6 protein family members with their target proteins at the plasma membrane may also occur in cis-. This has been observed during the activation of Syk kinase in immune cells or during the modulation of cholinergic receptor function in neurons (Syed, 2011 and references therein).

Members of the Ly6 protein family are widely expressed outside the immune system. In newts, expression of an Ly6-related molecule called Prod1 has been linked to regeneration as a marker for local identity. Another member of the Ly6 protein family, such as the secreted SLURP-1 protein, which lacks the GPI anchor, has been linked to the skin disorder Mal de Meleda. In mammals, recent transcriptome analyses have shown that Ly6-like proteins are also expressed by the blood-brain barrier forming endothelial cells (Daneman, 2010; Syed, 2011 and references therein).

Surprisingly, the Drosophila genome encodes a similar large number of Ly6 family proteins as the human genome (41 vs 45 family members) (Galat, 2008; Hijazi et al., 2009). The different proteins are thought to exert a large range of molecular functions. The cell-surface protein Sleepless is involved in the control of sleeping behavior, the Retroactive protein is involved in the assembly of tracheal luminal chitin, and the secreted protein Boudin is involved in septate junction formation in the tracheal system. As a common denominator, all different Ly6 family members are implicated in the recognition of extracellular cues, ranging from cell adhesion and signal transduction to cell activation processes (Syed, 2011).

GPI-linked proteins can in principle be localized to internal vesicles or to the plasma membrane. Unfortunately, specific antibodies to allow the detection of endogenous Coiled expression in tissues could not be generated. However, the fact that S2 cells transfected with UAScoiled were able to form aggregates and the fact that PI-PLC treatment resulted in the shedding of Coiled into the cell supernatant suggest that Coiled is indeed a cell-surface protein, as has been demonstrated for many other members of the Ly6 family. The closely related Boudin protein shows a broad cellular distribution and can act non-autonomously on septate junction formation (Hijazi, 2009; Syed, 2011 and references therein).

Coiled is crucially required for the formation of septate junctions among subperineurial glial cells. A core component of the Drosophila septate junction is NeurexinIV whose expression requires differential splicing. Correct membrane localization of NeurexinIV is brought about by the GPI-linked protein Contactin. Surprisingly, loss of Contactin is relatively well tolerated, and the BBB is only moderately affected. Recently, it was suggested that Coiled is also required for the correct trafficking of NeurexinIV, and Coiled was reported to exhibit a vesicular expression within cells (Nilton, 2010). This vesicular distribution may reflect recycling Coiled protein because membrane expression appears rather low. Based on the PI-PLC treatment and cell aggregation experiments, it is proposed that Coiled acts primarily at the cell surface. In line with this notion, a secreted, full-length N-terminally tagged Coiled protein cannot rescue the blood-brain barrier phenotype. In addition, it is interesting to note that the secreted Coiled protein does not appear to distribute in a random manner throughout the nervous system but rather appears to associate with other glial cells. Thus, either cortex and neuropil glial cells specifically phagocytose the Coiled protein or express a yet unknown Coiled receptor, possibly another member of the Ly6 family (Hijazi, 2009). The function of Coiled could therefore provide adhesiveness to prime the formation of septate junctions and to allow the subsequent integration of the NeurexinIV-based adhesive system. How Coiled and possibly other Ly6 domain proteins stabilize NeurexinIV to structure septate junctions must be addressed in future experiments (Syed, 2011).

The Ly6 protein coiled is required for septate junction and blood brain barrier organisation in Drosophila.

Genetic analysis of the Drosophila septate junctions has greatly contributed to the understanding of mechanisms controlling the assembly of these adhesion structures, which bear strong similarities with the vertebrate tight junctions and the paranodal septate junctions. These adhesion complexes share conserved molecular components and have a common function: the formation of paracellular barriers restraining the diffusion of solutes through epithelial and glial envelopes. This work characterises the function of the Drosophila cold gene, encoding a protein belonging to the Ly6 superfamily of extracellular ligands. Analysis of cold mutants shows that this gene is specifically required for the organisation of the septate junctions in epithelial tissues and in the nervous system, where its contribution is essential for the maintenance of the blood-brain barrier. cold acts in a cell autonomous way, and evidence is presented indicating that this protein could act as a septate junction component. The specific roles of cold is discussed and three other Drosophila members of the Ly6 superfamily that have been shown to participate in a non-redundant way in the process of septate junction assembly. It is proposed that vertebrate Ly6 proteins could fulfill analogous roles in tight junctions and/or paranodal septate junctions (Hijazi, 2011).

The profusion of Drosophila Ly6 paralogues (45 members) and the variety of their expression patterns suggest that mutants for these genes could a priori display the most various phenotypes, as it is the case for the three fly Ly6 genes characterised in so far: rtv, sss and bou. However, a recent report pointed out that three other Drosophila Ly6 proteins, Coiled, Crooked and Crimpled participate in a non redundant way in the same process as Bou: the organisation of epithelial septate junctions (Nilton, 2010). Genetic characterisation of cold mutants further confirms that this gene is required for SJ organisation in epithelial tissues, and shows by direct comparison with bou mutants that both elicit undistinguishable phenotypes. Still, besides their diagnostic set of 10 cysteines, the primary sequences of Bou, Coiled, Crooked and Crimpled are remarkably different, making impossible to predict a common molecular role. Given their structural divergences and the versatility of the Ly6 domain, they could in principle bind to different molecular partners. Analysis of bou cold double mutant embryos indicates that at least these two genes do not exert redundant functions during SJ assembly and cell polarity establishment. Thus, the available data are coherent with the idea that these proteins have non-exchangeable roles, despite their similarities at the phenotypic level. Interestingly, the four Ly6 genes implicated in the organisation of the fly SJ have highly conserved orthologues in other insects, such as the honey-bee (Hijazi, 2009 ), suggesting a hardwired role of these proteins in SJ assembly (Hijazi, 2011).

Analysis of embryos lacking both the cold zygotic and maternal contributions indicates that this gene is unlikely to have a role during the establishment of cell polarity. Thus, while some SJ components such as Yurt, NrxIV, Coracle and the Na⁺/K⁺ ATPase are also necessary for this process, the activity of Cold seems dispensable. Hence, it seems that this protein would participate in a genetic module whose role is solely required for the assembly of SJ. It will be interesting to test whether this also applies to the three other Ly6 genes affecting SJ organisation, as a differential requirement could provide hints facilitating the recognition of their specific partners (Hijazi, 2011).

A recent genetic screen identified cold as a gene required in the embryonic epidermis for efficient reestablishment of epithelial integrity upon injury (Campos, 2010). This observation indicates that the integrity of the whole SJ adhesion complex could be required for wound healing or, alternatively, that cold may have a specific role in this process. Further analysis of the role of the SJ adhesion structures during epithelial repair will allow clarification of this issue. In any case, this observation shows that upcoming functional analysis of the Drosophila Ly6 proteins is likely to contribute to a better understanding of many developmental and physiological processes in which this versatile module has been co-opted (Hijazi, 2011).

Previous studies in S2 cells pointed out that a Cold tagged version expressed in these cells accumulates in endocytic vesicles (Nilton, 2010) . The localisation of a functional FLAG-Cold fusion protein was examined both in S2 cells and in developing tissues containing SJ. The findings are consistent with the idea that Cold, predicted to be GPI anchored by the bigPI software, is associated not only with the endoplasmic reticulum and internal vesicles but also with the plasma membrane. In the salivary glands, a small amount of FLAG-Cold was observed stably associated with SJ containing regions, as if making part of a complex localising to this membrane compartment. Interestingly, a similar accumulation has been observed with a HA-Bou tagged version in the same tissue (Hijazi, 2009). It is thus possible that a small subset of both proteins could contribute to the organisation of the SJ by interacting with each other and/or with other SJ components. However, it is premature to conclude that Cold function is circumscribed to the lateral membrane region containing the SJ, as other valid alternatives exist. In fact, the FLAG-Cold protein was also seen in other subcellular compartments, and it is difficult to ascertain where it exerts its primary activity. For instance, it has been shown that the SJ component NrxIV is re-localised to internal vesicles in cold mutant embryos (Nilton, 2010). Although this phenotype is also observed in embryos lacking known SJ components such as Coracle and Nrv2, the Ly6 proteins could indeed play a role in the vesicular trafficking of these proteins or in their preassembly into larger macro-complexes en route to the membrane. As the intracellular traffic seems to play a key role in the early assembly of the SJ, it will be interesting to compare the paths followed by Ly6 proteins and known SJ components during the formation of these structures. Concerning the traffic of the Ly6 proteins themselves, it is clear that Cold differs from Bou in two related aspects: it behaves in a cell autonomous way, and no evidence was found indicating that this protein could travel from cell to cell. Thus, although these proteins may meet at the level of the SJ or in other subcellular compartments, these observations implicate that they do not always traffic together. It will be interesting to analyse whether this differential behaviour provides a rationale for their non-exchangeable roles (Hijazi, 2011).

The results show that cold is expressed in a subset of glial cells and is required for organisation of the blood-brain-barrier in the Drosophila nervous system. Thus, it is possible that vertebrate members of the Ly6 superfamily could fulfil an analogous role in the formation of the paranodal junctions existing in the contact areas between axons and Schwann cells. The high variability observed in the Ly6 domains primary sequence precludes identification of vertebrate orthologues corresponding to the Drosophila genes. However, the genetic networks in which these proteins are implicated could be better conserved, as insect SJ and paranodal junctions share a significant number of components. Thus, future functional studies in Drosophila and vertebrates may reveal analogous roles for apparently unrelated Ly6 proteins, as it is the case for the four Drosophila Ly6 members participating in SJ assembly (Hijazi, 2011).

Multispecies Analysis of Expression Pattern Diversification in the Recently Expanded Insect Ly6 Gene Family

Gene families often consist of members with diverse expression domains reflecting their functions in a wide variety of tissues. However, how the expression of individual members, and thus their tissue-specific functions, diversified during the course of gene family expansion is not well understood. This study approached this question through the analysis of the duplication history and transcriptional evolution of a rapidly expanding subfamily of insect Ly6 genes. Different insect genomes were examined and seven Ly6 genes were identified that have originated from a single ancestor through sequential duplication within the higher Diptera. It was then determined how the original embryonic expression pattern of the founding gene diversified by characterizing its tissue-specific expression in the beetle Tribolium castaneum, the butterfly Bicyclus anynana, and the mosquito Anopheles stephensi and those of its duplicates in three higher dipteran species, representing various stages of the duplication history (Megaselia abdita, Ceratitis capitata, and Drosophila melanogaster). The results revealed that frequent neofunctionalization episodes contributed to the increased expression breadth of this subfamily and that these events occurred after duplication and speciation events at comparable frequencies. In addition, at each duplication node, asymmetric expression divergence was consistently found. One paralog inherited most of the tissue-specificities of the founder gene, whereas the other paralog evolved drastically reduced expression domains. This approach attests to the power of combining a well-established duplication history with a comprehensive coverage of representative species in acquiring unequivocal information about the dynamics of gene expression evolution in gene families (Tanaka, 2015).

Crooked, coiled and crimpled are three Ly6-like proteins required for proper localization of septate junction components.

Cellular junction formation is an elaborate process that is dependent on the regulated synthesis, assembly and membrane targeting of constituting components. This study reports on three Drosophila Ly6-like proteins essential for septate junction (SJ) formation. SJs provide a paracellular diffusion barrier and appear molecularly and structurally similar to vertebrate paranodal septate junctions. Crooked (Crok), a small GPI-anchored Ly6-like protein, is required for septa formation and barrier functions. In embryos that lack Crok, SJ components are produced but fail to accumulate at the plasma membrane. Crok is detected in intracellular puncta and acts tissue-autonomously, which suggests that it resides in intracellular vesicles to assist the cell surface localization of SJ components. In addition, it was demonstrated that two related Ly6 proteins, Coiled (Cold) and Crimpled (Crim), are required for SJ formation and function in a tissue-autonomous manner, and that Cold also localizes to intracellular vesicles. Specifically, Crok and Cold are required for correct membrane trafficking of Neurexin IV, a central SJ component. The non-redundant requirement for Crok, Cold, Crim and Boudin (Bou; another Ly6 protein that was recently shown to be involved in SJ formation) suggests that members of this conserved family of proteins cooperate in the assembly of SJ components, possibly by promoting core SJ complex formation in intracellular compartments associated with membrane trafficking (Nilton, 2009).

Ly6 proteins constitute large protein families in both vertebrates and insects. In mammals, they are expressed in cells of hematopoetic origin, the brain, vascular epithelium, kidney tubular epithelium, lung, keratinocytes, stomach, testis and prostate. Reflecting their differential expression, Ly6 proteins are used in diverse biological processes. Apart from acting as GPI-linked cell accessory proteins of the immune system, vertebrate Ly6 proteins function in the modulation of nicotinic acetylcholine receptors, remodelling of the extracellular matrix during skeletal muscle regeneration , and lipolytic processing of triglyceride-rich lipoproteins by binding lipoprotein lipase. The presence of a GPI-anchor in Ly6 molecules, a lipid anchor that tethers the proteins on the outer leaflet of the membrane, also suggests that Ly6 proteins can aggregate in lipid rafts to alter the activity of associated proteins (Nilton, 2009).

The Drosophila Ly6-like genes also exhibit a diverse tissue-specific distribution during development, with subsets of genes showing similar tissue expression, suggesting that they participate in similar biological processes. Indeed, five of the 18 Drosophila Ly6-like genes are expressed in a similar pattern in the developing ectoderm, and at least four are required for SJ formation, including bou (Hijazi, 2009), crok, crim and cold. The only other GPI-linked Drosophila Ly6 protein studied so far is quiver (qvr; also known as sleepless), which is required for sleep and appears to affect the levels of the voltage-dependent potassium channel Shaker (Nilton, 2009 and references therein).

Phenotypic analyses of crok mutants show that Crok is required for plasma membrane accumulation of SJ components. As SJ components were detected in the tracheal cytoplasm of stage 15 crok mutant embryos and protein analyses on immunoblots show that ATPα and Nrx-VI are present in crok mutants, it is conclude that Crok is not required for the synthesis of SJ components. Moreover, elevated levels of ATP? and Nrx-VI were detected in mutant embryonic extracts, despite an apparent reduction of immunofluorescence staining for these proteins, suggesting that these components are more easily solubilized in the mutant embryos. It thus appears that Crok is required for the formation of SJ complexes at the correct plasma membrane domain (Nilton, 2009).

The function of both Crok and Cold appears to be necessary for the efficient incorporation of Nrx-IV into a stable SJ-associated complex. Upon loss of Crok and Cold, Nrx-IV-GFP accumulates in large intracellular vesicles. A similar situation occurs upon loss of Cora, which interacts with the cytoplasmic tail of Nrx-IV. The presence of fluid-phase dextran in these vesicles suggests that the Nrx-IV-GFP puncta in crok and cold mutants represent endocytosed protein, possibly on route to degradation in lysosomal compartments. Consistent with this idea, subsets of the Nrx-IV vesicles in cold mutants were observed to colocalize with endocytic markers, including Rab5 (early endosomes), Rab11 (recycling endosomes), Hrs (late endosomes) and Dor (lysosomes). As other known SJ components were not detected in these vesicles, it appears that they contain SJ subcomplexes that include Nrx-IV and Cora. This specificity could suggest either that Nrx-IV and interacting proteins are more sensitive than are other components to disruption in SJ assembly, or that Crok and Cold are specifically involved in the stable integration of Nrx-IV and interacting proteins into the SJ complex. Further experiments will be required to discern these alternative possibilities (Nilton, 2009).

Bou, Crok and Cold all appear to accumulate in intracellular membrane compartments. Previous studies have shown that uPAR, an extensively studied GPI-linked protein with two LU domains, is endocytosed and recycled, and that this trafficking is essential for its function. Consistent with this idea, it was found that Cold colocalizes with dextran-labelled vesicles in cultured cells. In addition, although Bou appears to accumulate in the perinuclear cytoplasm (Hijazi, 2009), the non-autonomous behaviour of Bou suggests that it travels to the plasma membrane. Like Bou, Crok shows an apparent association with internal membrane compartments, particularly the ER. The Crok antiserum does not detect endogenous Crok at high levels, and it is possible that Crok in addition associates transiently with the cell surface. So far it has not been possible to conclusively address a possible colocalizaiton of Nrx-IV with Crok or Cold, or with markers for endosomal compartments, and it is currently unclear whether the Ly6 proteins act in the sorting, trafficking or pre-assembly of SJ components prior to their transport to the site of junction assembly, or in an endocytic recycling of the components (Nilton, 2009).

The non-redundant requirement for four Ly6-like proteins in SJ assembly is intriguing and coherent with the need for multiple Ly6-like proteins in the allosteric modulation of nicotinic acetylcholine receptor (nAChR) functions. These Ly6-like proteins include Lynx1 and possibly Lypd6 in neurons, and the secreted proteins Slurp1 and Slurp2 in the ectoderm. It has further been suggested that the lynx-nAChR interactions occur during receptor biosynthesis and maturation in the endoplasmic reticulum, a main site for assembly of the multi-subunit membrane proteins of nAChRs. By analogy, the Drosophila Ly6-like proteins might assume roles as allosteric modulators of multiprotein SJ complexes to promote their functional association (Nilton, 2009).

Together, the analyses of Crok, Crim, Cold and Bou highlight a central task for Ly6 proteins in SJ formation that might also be essential for vertebrate paranodal junction assembly. Identification of their ligands and the subcellular site of action should contribute further understanding of how highly ordered, multi-protein complexes form along precise subdomains of the plasma membrane (Nilton, 2009).

Search PubMed for articles about Drosophila coiled

Campos, I., et al. (2010). Genetic screen in Drosophila melanogaster uncovers a novel set of genes required for embryonic epithelial repair. Genetics 184: 129–140. PubMed ID: 19884309

Daneman R, et al. (2010) The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS One 5: e13741. PubMed ID: 21060791

Hijazi, A., Haenlin, M., Waltzer, L. and Roch. F. (2011). The Ly6 protein coiled is required for septate junction and blood brain barrier organisation in Drosophila. PLoS One. 6(3): e17763. PubMed ID: 21423573

Kimberley, F. C., Sivasankar, B. and Paul Morgan, B (2007) Alternative roles for CD59. Mol Immunol 44: 73–81. PubMed ID: 16884774

Huang, Y., Fedarovich, A., Tomlinson, S. and Davies, C. (2007). Crystal structure of CD59: implications for molecular recognition of the complement proteins C8 and C9 in the membrane-attack complex. Acta. Crystallogr. D Biol. Crystallogr. 63: 714–721. PubMed ID: 17505110

Meri S, et al. (1990) Human protectin (CD59), an 18,000–20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. Immunology 71: 1–9. PubMed ID: 1698710

Nilton, A., et al. (2010). Crooked, coiled and crimpled are three Ly6-like proteins required for proper localization of septate junction components. Development 137(14): 2427-37. PubMed ID: 20570942

Syed, M. H., Krudewig, A., Engelen, D., Stork, T. and Klämbt, C. (2011). The CD59 family member Leaky/Coiled is required for the establishment of the blood-brain barrier in Drosophila. J Neurosci. 31(21): 7876-85. PubMed ID: 21613501

Tanaka, K., Diekmann, Y., Hazbun, A., Hijazi, A., Vreede, B., Roch, F. and Sucena, E. (2015). Multispecies Analysis of Expression Pattern Diversification in the Recently Expanded Insect Ly6 Gene Family. Mol Biol Evol 32(7): 1730-1747. PubMed ID: 25743545

Tsetlin, V. (1999). Snake venom alpha-neurotoxins and other 'three-finger' proteins. Eur J. Biochem. 264: 281–286. PubMed ID: 10491072

date revised: 2 October 2011

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