Functional Analysis of the Fibrinogen-Related scabrous Gene From Drosophila melanogaster Identifies Potential Effector and Stimulatory Protein Domains

Lee, E-Chiang; Yu, Sung-Yun; Hu, Xiaoxi; Mlodzik, Marek; Baker, Nicholas E.

doi:10.1093/genetics/150.2.663

Cited by 19 publications

(1 citation statement)

References 28 publications

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“…Finally, gC-containing chains (g, Bb-g, Ang2 -g) and complexes [AagBb -g] were abundantly secreted, whereas gC-lacking fibrinogen molecules [AaBbg -Bb] were retained within cells, revealing a positive, if not essential role of aC in secretion. These results are consistent with those of a study on chimeras combining the N-terminus of the Drosophila FReD-containing scabrous protein and human fibrinogen C-terminus (38). In this case, scabrous-a E and -g were secreted, whereas scabrous-Bb was arrested in the secretory pathway.…”

Section: Discussionsupporting

confidence: 91%

Quality control of fibrinogen secretion in the molecular pathogenesis of congenital afibrinogenemia

Vu¹,

Sanza²,

Caille³

et al. 2005

Human Molecular Genetics

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Congenital afibrinogenemia is a rare bleeding disorder characterized by the absence in circulation of fibrinogen, a hexamer composed of two sets of three polypeptides (Aalpha, Bbeta and gamma). Each polypeptide is encoded by a distinct gene, FGA, FGB and FGG, all three clustered in a region of 50 kb on 4q31. A subset of afibrinogenemia mutations has been shown to specifically impair fibrinogen secretion, but the underlying molecular mechanisms remained to be elucidated. Here, we show that truncation of the seven most C-terminal residues (R455-Q461) of the Bbeta chain specifically inhibits fibrinogen secretion. Expression of additional mutants and structural modelling suggests that neither the last six residues nor R455 is crucial per se for secretion, but prevent protein misfolding by protecting hydrophobic residues in the betaC core. Immunofluorescence and immuno-electron microscopy studies indicate that secretion-impaired mutants are retained in a pre-Golgi compartment. In addition, expression of Bbeta, gamma and angiopoietin-2 chimeric molecules demonstrated that the betaC domain prevents the secretion of single chains and complexes, whereas the gammaC domain allows their secretion. Our data provide new insight into the mechanisms accounting for the quality control of fibrinogen secretion and confirm that mutant fibrinogen retention is one of the pathological mechanisms responsible for congenital afibrinogenemia.

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Section: Discussionsupporting

confidence: 91%

Quality control of fibrinogen secretion in the molecular pathogenesis of congenital afibrinogenemia

Vu¹,

Sanza²,

Caille³

et al. 2005

Human Molecular Genetics

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Scabrous overexpression in the eye affects R3/R4 cell fate specification and inhibits notch signaling

Muñoz-Soriano

Santos

Durupt

et al. 2015

Developmental Dynamics

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Background: Planar cell polarity (PCP) in the Drosophila eye is generated when immature ommatidial preclusters acquire opposite chirality in the dorsal and ventral halves of the eye imaginal disc and rotate 90°toward the equator. The scabrous (sca) gene is involved in R8 differentiation and in the correct spacing of ommatidial clusters in eye imaginal discs, but it was also suggested to be required during ommatidial rotation. However, no clear relationships between sca and other genes involved in the process were established. Results: To explore the role of Sca in PCP establishment, we performed an RNAibased modifier genetic screen using the rough eye phenotype of sca-overexpressing flies. We found that sca overexpression mainly affects R3/R4 cell specification as it was reported in Notch mutants. Of the 86 modifiers identified in the screen, genes encoding components of Notch signaling and proteins involved in intracellular transport were of particular interest. Conclusions: These and other results obtained with a reporter line of Notch activity indicate that sca overexpression antagonizes Notch signaling in the Drosophila eye, and are inconsistent with Sca being an ommatidial rotation-specific factor. We also found that microtubule motors and other proteins involved in intracellular transport are related with Sca function. Developmental Dynamics 245:166-174, 2016. V C 2015 Wiley Periodicals, Inc.

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scabrous Modifies Epithelial Cell Adhesion and Extends the Range of Lateral Signalling during Development of the Spaced Bristle Pattern in Drosophila

Renaud

Simpson

2001

Developmental Biology

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The role of scabrous (sca) in the evenly spaced bristle pattern of Drosophila is explored. Loss-of-function of sca results in development of an excess of bristles. Segregation of alternately spaced bristle precursors and epidermal cells from a group of equipotential cells relies on lateral inhibition mediated by Notch and Delta (Dl). In this process, presumptive bristle precursors inhibit the neural fate of neighbouring cells, causing them to adopt the epidermal fate. We show that Dl, a membrane-bound ligand for Notch, can inhibit adjacent cells, in direct contact with the precursor, in the absence of Sca. In contrast, inhibition of cells not adjacent to the precursor requires, in addition, Sca, a secreted molecule with a fibrinogen-related domain. Over-expression of Sca in a wild-type background, leads to increased spacing between bristles, suggesting that the range of signalling has been increased. scabrous acts nonautonomously, and we present evidence that, during bristle precursor segregation, Sca is required to maintain the normal adhesive properties of epithelial cells. The possible effects of such changes on the range of signalling are discussed. We also show that the sensory organ precursors extend numerous fine cytoplasmic extensions bearing Dl molecules, and speculate on a possible role for these structures during signalling.

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Functional Analysis of the Fibrinogen-Related scabrous Gene From Drosophila melanogaster Identifies Potential Effector and Stimulatory Protein Domains

Cited by 19 publications

References 28 publications

Quality control of fibrinogen secretion in the molecular pathogenesis of congenital afibrinogenemia

Quality control of fibrinogen secretion in the molecular pathogenesis of congenital afibrinogenemia

Scabrous overexpression in the eye affects R3/R4 cell fate specification and inhibits notch signaling

scabrous Modifies Epithelial Cell Adhesion and Extends the Range of Lateral Signalling during Development of the Spaced Bristle Pattern in Drosophila

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