The Heparan Sulfate Proteoglycans Dally-like and Syndecan Have Distinct Functions in Axon Guidance and Visual-System Assembly in Drosophila

Rawson, Jonathan M. O.; Dimitroff, Brian; Johnson, Karl G.; Rawson, Jaime M.; Ge, Xuecai; Vactor, David Van; Selleck, Scott B.

doi:10.1016/j.cub.2005.03.039

Cited by 60 publications

(61 citation statements)

References 20 publications

(2 reference statements)

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“…Among the four B52 targets found by both the genomic SELEX and splicing microarray analyses (fur1, lola, RhoGAp16F, and Syndecan), only lola (longitudinals lacking) has been identified in the present study. While these observations possibly reflect, as observed for fur2 (38), the lack of expression of fur1 in R cells, the situation is more surprising in the case of Syndecan, since expression of this gene has been detected in R-cell axons (35). This target, however, was not validated in B52 mutant larvae (22), suggesting that the event detected on splicing microarrays is restricted to specific tissues.…”

Section: Discussionmentioning

confidence: 87%

The SR Family Proteins B52 and dASF/SF2 Modulate Development of the Drosophila Visual System by Regulating Specific RNA Targets

Gabut

Déjardin

Tazi

et al. 2007

Molecular and Cellular Biology

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Deciphering the role of alternative splicing in developmental processes relies on the identification of key genes whose expression is controlled by splicing regulators throughout the growth of a whole organism. Modulating the expression levels of five SR proteins in the developing eye of Drosophila melanogaster revealed that these splicing factors induce various phenotypic alterations in eye organogenesis and also affect viability. Although the SR proteins dASF/SF2 and B52 caused defects in ommatidia structure, only B52 impaired normal axonal projections of photoreceptors and neurogenesis in visual ganglia. Microarray analyses revealed that many transcripts involved in brain organogenesis have altered splicing profiles upon both loss and gain of B52 function. Conversely, a large proportion of transcripts regulated by dASF/SF2 are involved in eye development. These differential and specific effects of SR proteins indicate that they function to confer accuracy to developmental gene expression programs by facilitating the cell lineage decisions that underline the generation of tissue identities.Alternative pre-mRNA splicing represents a powerful means of allowing higher eukaryotes to increase their proteome diversity and to regulate gene expression in a developmentand tissue-specific way (31). Among the different factors involved in regulation of alternative splicing, members of the SR family are among the most extensively studied (4). SR proteins are essential splicing factors involved in early steps of spliceosome assembly as well as regulators of alternative splicing. Members of the SR family were also recently shown to participate in mRNA export (20,26), degradation (27, 53), protein translation (39), and maintenance of genome stability (28). SR proteins share a very similar domain organization consisting of one or two RNA recognition motifs at the N terminus and a region rich in arginine-serine dipeptides (RS domain) at the C terminus (18). However, they recognize distinct exonic splicing enhancer elements and are not functionally redundant in vitro or in vivo (5, 30). Evidence that SR proteins exert essential roles in vivo was first reported for B52/SRp55 in Drosophila melanogaster. Indeed, B52-null mutants do not develop past the second-instar larval stage even though the splicing of several endogenous transcripts tested was not significantly altered (37). Later, gene targeting of SF2/ASF in the DT40 chicken B-cell line and of SRp20 in mice was reported to cause lethality (21, 50). More recently, conditional deletion of SC35 in the thymus and in the heart was shown to cause a defect in T-cell maturation and to induce dilated cardiomyopathy in mice (13, 49). Interestingly, a similar deletion of SF2/ ASF in the heart resulted in a significantly different phenotype (51), demonstrating that these two related splicing factors play fundamentally distinct roles in cardiac tissue.While members of the SR protein family have been well characterized at the biochemical level, relatively little is known concerning their ...

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Section: Discussionmentioning

confidence: 87%

The SR Family Proteins B52 and dASF/SF2 Modulate Development of the Drosophila Visual System by Regulating Specific RNA Targets

Gabut

Déjardin

Tazi

et al. 2007

Molecular and Cellular Biology

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“…Such studies suggest that the GAG chains mediate some biological effects and that the core proteins mediate others (17,28). For mammals, in vivo studies have been more limited.…”

Section: Discussionmentioning

confidence: 99%

Host Glycosaminoglycan Confers Susceptibility to Bacterial Infection in Drosophila melanogaster

et al. 2009

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Many pathogens engage host cell surface glycosaminoglycans, but redundancy in pathogen adhesins and host glycosaminoglycan-anchoring proteins (heparan sulfate proteoglycans) has limited the understanding of the importance of glycosaminoglycan binding during infection. The alpha C protein of group B streptococcus, a virulence determinant for this neonatal human pathogen, binds to host glycosaminoglycan and mediates the entry of bacteria into human cells. We studied alpha C protein-glycosaminoglycan binding in Drosophila melanogaster, whose glycosaminoglycan repertoire resembles that of humans but whose genome includes only three characterized membrane heparan sulfate proteoglycan genes. The knockdown of glycosaminoglycan polymerases or of heparan sulfate proteoglycans reduced the cellular binding of alpha C protein. The interruption of alpha C protein-glycosaminoglycan binding was associated with longer host survival and a lower bacterial burden. These data indicate that the glycosaminoglycan-alpha C protein interaction involves multiple heparan sulfate proteoglycans and impairs bacterial killing. Host glycosaminoglycans, anchored by multiple proteoglycans, thereby determine susceptibility to infection. Because there is homology between Drosophila and human glycosaminoglycan/proteoglycan structures and many pathogens express glycosaminoglycan-binding structures, our data suggest that interfering with glycosaminoglycan binding may protect against infections in humans.Streptococcus agalactiae (group B streptococcus [GBS]) commonly colonizes human mucosal surfaces and also causes devastating invasive infections, particularly in neonates. The main identified mammalian host defense against GBS is opsonophagocytosis, requiring phagocytes, complement, and specific antibody. GBS virulence determinants include surface structures such as capsular polysaccharide, cytolysin, and the protein designated Dalanylation of lipoteichoic acid (DltA) (10,22,25). Protecting the organism from phagocytosis, capsular polysaccharide is a highmolecular-weight polymer composed of more than 100 repeating pentasaccharide units, each with a terminal sialic acid moiety. Cytolysin promotes enhanced GBS survival during infection by contributing to phagocyte cytolysis and apoptosis and by helping shield GBS from oxidative damage (18). Deficiency in DltA is associated with increased susceptibility to phagocytosis and to antimicrobial peptides (25).Alpha C protein (ACP) is an important GBS virulence determinant that binds to host cell glycosaminoglycan (GAG) and mediates bacterial entry into human cells (3, 4, 5) in vitro. We aimed to further characterize the host cell receptor and to determine the importance of the ACP-GAG interactions in vivo.GAGs are highly sulfated modified polysaccharide polymers anchored in the cell membrane by a protein core as a heparan sulfate proteoglycan (HSPG). Among the most abundant cell surface GAGs are heparan sulfate (HS) and chondroitin sulfate (CS). HS consists of iduronic or glucuronic acid and Nacetylglucosamine...

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“…In invertebrates, syndecan has been studied extensively in both Drosophila and Caenorhabditis elegans neural development and plays key roles in repulsive axon guidance mediated by slit-Robo signaling and in synaptogenesis at the neuromuscular junction (Johnson et al 2004;Steigemann et al 2004;Fox and Zinn 2005;Rawson et al 2005). In Drosophila, dally-like has been implicated in visual system and CNS axon guidance (Johnson et al 2004;Rawson et al 2005). Both syndecan and dally-like are expressed on Drosophila embryonic CNS axons and are found in both the anterior and posterior commissures of each segment (Johnson et al 2004).…”

Section: Specificity Of Hspg-mediated Modulation Of Sema-1a Signalingmentioning

confidence: 99%

The extracellular matrix proteoglycan perlecan facilitates transmembrane semaphorin-mediated repulsive guidance

et al. 2012

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The Drosophila transmembrane semaphorin-1a (Sema-1a) is a repulsive guidance cue that uses the Plexin A (PlexA) receptor during neural development. Sema-1a is required in axons to facilitate motor axon defasciculation at guidance choice points. We found that mutations in the trol gene strongly suppress Sema-1a-mediated repulsive axon guidance. trol encodes the phylogenetically conserved secreted heparan sulfate proteoglycan (HSPG) perlecan, a component of the extracellular matrix. Motor axon guidance defects in perlecan mutants resemble those observed in Sema-1a-and PlexA-null mutant embryos, and perlecan mutants genetically interact with PlexA and Sema-1a. Perlecan protein is found in both the CNS and the periphery, with higher expression levels in close proximity to motor axon trajectories and pathway choice points. Restoring perlecan to mutant motor neurons rescues perlecan axon guidance defects. Perlecan augments the reduction in phospho-focal adhesion kinase (phospho-FAK) levels that result from treating insect cells in vitro with Sema-1a, and genetic interactions among integrin, Sema-1a, and FAK in vivo support an antagonistic relationship between Sema-1a and integrin signaling. Therefore, perlecan is required for Sema-1a-PlexA-mediated repulsive guidance, revealing roles for extracellular matrix proteoglycans in modulating transmembrane guidance cue signaling during neural development.

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The Heparan Sulfate Proteoglycans Dally-like and Syndecan Have Distinct Functions in Axon Guidance and Visual-System Assembly in Drosophila

Cited by 60 publications

References 20 publications

The SR Family Proteins B52 and dASF/SF2 Modulate Development of the Drosophila Visual System by Regulating Specific RNA Targets

The SR Family Proteins B52 and dASF/SF2 Modulate Development of the Drosophila Visual System by Regulating Specific RNA Targets

Host Glycosaminoglycan Confers Susceptibility to Bacterial Infection in Drosophila melanogaster

The extracellular matrix proteoglycan perlecan facilitates transmembrane semaphorin-mediated repulsive guidance

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