The Role of Glypicans in Wnt Inhibitory Factor-1 Activity and the Structural Basis of Wif1's Effects on Wnt and Hedgehog Signaling

被引:35
作者
Avanesov, Andrei [1 ,2 ]
Honeyager, Shawn M. [1 ]
Malicki, Jarema [3 ]
Blair, Seth S. [1 ]
机构
[1] Univ Wisconsin, Dept Zool, Madison, WI 53706 USA
[2] Univ Wisconsin, Genet Training Program, Madison, WI USA
[3] Tufts Univ, Div Craniofacial & Mol Genet, Boston, MA 02111 USA
关键词
WINGLESS MORPHOGEN GRADIENT; HEPARAN-SULFATE PROTEOGLYCANS; LUNG-CANCER CELLS; DALLY-LIKE; ZEBRAFISH GASTRULATION; PROMOTER DEMETHYLATION; DROSOPHILA DEVELOPMENT; CONVERGENT EXTENSION; TRANSCRIPTION FACTOR; CELLULAR-RESPONSES;
D O I
10.1371/journal.pgen.1002503
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Proper assignment of cellular fates relies on correct interpretation of Wnt and Hedgehog (Hh) signals. Members of the Wnt Inhibitory Factor-1 (WIF1) family are secreted modulators of these extracellular signaling pathways. Vertebrate WIF1 binds Wnts and inhibits their signaling, but its Drosophila melanogaster ortholog Shifted (Shf) binds Hh and extends the range of Hh activity in the developing D. melanogaster wing. Shf activity is thought to depend on reinforcing interactions between Hh and glypican HSPGs. Using zebrafish embryos and the heterologous system provided by D. melanogaster wing, we report on the contribution of glypican HSPGs to the Wnt-inhibiting activity of zebrafish Wif1 and on the protein domains responsible for the differences in Wif1 and Shf specificity. We show that Wif1 strengthens interactions between Wnt and glypicans, modulating the biphasic action of glypicans towards Wnt inhibition; conversely, glypicans and the glypican-binding "EGF-like" domains of Wif1 are required for Wif1's full Wnt-inhibiting activity. Chimeric constructs between Wif1 and Shf were used to investigate their specificities for Wnt and Hh signaling. Full Wnt inhibition required the "WIF" domain of Wif1, and the HSPG-binding EGF-like domains of either Wif1 or Shf. Full promotion of Hh signaling requires both the EGF-like domains of Shf and the WIF domains of either Wif1 or Shf. That the Wif1 WIF domain can increase the Hh promoting activity of Shf's EGF domains suggests it is capable of interacting with Hh. In fact, full-length Wif1 affected distribution and signaling of Hh in D. melanogaster, albeit weakly, suggesting a possible role for Wif1 as a modulator of vertebrate Hh signaling.
引用
收藏
页数:16
相关论文
共 106 条
[1]   The wingless morphogen gradient is established by the cooperative action of Frizzled and Heparan Sulfate Proteoglycan receptors [J].
Baeg, GH ;
Selva, EM ;
Goodman, RM ;
Dasgupta, R ;
Perrimon, N .
DEVELOPMENTAL BIOLOGY, 2004, 276 (01) :89-100
[2]  
BAKER NE, 1988, DEVELOPMENT, V102, P489
[3]  
Barresi MJF, 2000, DEVELOPMENT, V127, P2189
[4]   Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion [J].
Bellaiche, Y ;
The, I ;
Perrimon, N .
NATURE, 1998, 394 (6688) :85-88
[5]   Wing vein Patterning in Drosophila and the analysis of intercellular signaling [J].
Blair, Seth S. .
ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 2007, 23 :293-319
[6]   A ROLE FOR THE SEGMENT POLARITY GENE SHAGGY-ZESTE WHITE-3 IN THE SPECIFICATION OF REGIONAL IDENTITY IN THE DEVELOPING WING OF DROSOPHILA [J].
BLAIR, SS .
DEVELOPMENTAL BIOLOGY, 1994, 162 (01) :229-244
[7]   Genetic mosaic techniques for studying Drosophila development [J].
Blair, SS .
DEVELOPMENT, 2003, 130 (21) :5065-5072
[8]   Abrogation of heparan sulfate synthesis in Drosophila disrupts the Wingless, Hedgehog and Decapentaplegic signaling pathways [J].
Bornemann, DJ ;
Duncan, JE ;
Staatz, W ;
Selleck, S ;
Warrior, R .
DEVELOPMENT, 2004, 131 (09) :1927-1938
[9]  
BRAND AH, 1993, DEVELOPMENT, V118, P401
[10]   Antagonistic interactions between Wingless and decapentaplegic responsible for dorsal-ventral pattern in the Drosophila leg [J].
Brook, WJ ;
Cohen, SM .
SCIENCE, 1996, 273 (5280) :1373-1377