Uif, a Large Transmembrane Protein with EGF-Like Repeats, Can Antagonize Notch Signaling in Drosophila

State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
PLoS ONE (Impact Factor: 3.23). 04/2012; 7(4):e36362. DOI: 10.1371/journal.pone.0036362
Source: PubMed


Notch signaling is a highly conserved pathway in multi-cellular organisms ranging from flies to humans. It controls a variety of developmental processes by stimulating the expression of its target genes in a highly specific manner both spatially and temporally. The diversity, specificity and sensitivity of the Notch signaling output are regulated at distinct levels, particularly at the level of ligand-receptor interactions.
Here, we report that the Drosophila gene uninflatable (uif), which encodes a large transmembrane protein with eighteen EGF-like repeats in its extracellular domain, can antagonize the canonical Notch signaling pathway. Overexpression of Uif or ectopic expression of a neomorphic form of Uif, Uif*, causes Notch signaling defects in both the wing and the sensory organ precursors. Further experiments suggest that ectopic expression of Uif* inhibits Notch signaling in cis and acts at a step that is dependent on the extracellular domain of Notch. Our results suggest that Uif can alter the accessibility of the Notch extracellular domain to its ligands during Notch activation.
Our study shows that Uif can modulate Notch activity, illustrating the importance of a delicate regulation of this signaling pathway for normal patterning.

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Available from: Renjie Jiao, Dec 27, 2013
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    • "Flies deficient in furrowed exhibited disrupted development of compound eyes and bristles (Chin and Mlodzik, 2013; Leshko-Lindsay and Corces, 1997). Functions of the gene uninflatable (uif, CTL-X3 ortholog) were implied in two manners: uif deficient flies displayed deficiencies in tracheal growth, tracheal cuticle molting and trachea inflation during embryogenesis; uif antagonizes the Notch signaling pathway by modulating ligand accessibility to the extracellular domain of Notch (Xie et al., 2012; Zhang and Ward, 2009). Acting with neuroglian and neurexin IV, contactin (CTL-X4 ortholog) is essential for septate junction organization in epithelial and neuronal cells, normal blood-nerve barrier in peripheral nervous system, and bloodebrain barrier functions (Banerjee et al., 2006; Faivre-Sarrailh et al., 2004; Stork et al., 2008). "
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    ABSTRACT: C-type lectins (CTLs) are a large family of Ca(2+)-dependent carbohydrate-binding proteins recognizing various glycoconjugates and functioning primarily in immunity and cell adhesion. We have identified 34 CTLDP (for CTL-domain protein) genes in the Manduca sexta genome, which encode proteins with one to three CTL domains. CTL-S1 through S9 (S for simple) have one or three CTL domains; immulectin-1 through 19 have two CTL domains; CTL-X1 through X6 (X for complex) have one or two CTL domains along with other structural modules. Nine simple CTLs and seventeen immulectins have a signal peptide and are likely extracellular. Five complex CTLs have both an N-terminal signal peptide and a C-terminal transmembrane region, indicating that they are membrane anchored. Immulectins exist broadly in Lepidoptera and lineage-specific gene duplications have generated three clusters of fourteen genes in the M. sexta genome, thirteen of which have similar expression patterns. In contrast to the family expansion, CTL-S1∼S6, S8, and X1∼X6 have 1:1 orthologs in at least four lepidopteran/dipteran/coleopteran species, suggestive of conserved functions in a wide range of holometabolous insects. Structural modeling suggests the key residues for Ca(2+)-dependent or independent binding of certain carbohydrates by CTL domains. Promoter analysis identified putative κB motifs in eighteen of the CTL genes, which did not have a strong correlation with immune inducibility in the mRNA or protein levels. Together, the gene identification, sequence comparisons, structure modeling, phylogenetic analysis, and expression profiling establish a solid foundation for future studies of M. sexta CTL-domain proteins. Copyright © 2014 Elsevier Ltd. All rights reserved.
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    • ") into the nucleus to activate Notch target gene transcription with the assistance of Su(H) and co-activator Mastermind (Mam) (Bray, 2006; Artavanis-Tsakonas and Muskavitch, 2010). Despite the relative simplicity of primary Notch signaling, the presence of a large number of fine-tuning regulators at different levels, from the outside of the cell membrane to the nucleus, dramatically increases the complexity of Notch pathway outputs and its cellular responses, thus controlling a wide range of developmental processes (Neumann and Cohen, 1998; Acar et al., 2008; Hautbergue et al., 2009; Kim et al., 2009; Xie et al., 2012). At the nuclear level, recent findings suggest that chromatin-associated regulatory mechanisms are important for proper Notch target gene expression (Bray et al., 2005; Kugler and Nagel, 2007; Moshkin et al., 2009; Duan et al., 2011; Mulligan et al., 2011; Domanitskaya and Schüpbach, 2012; Endo et al., 2012). "
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