Down-regulation of chondroitin 4-O-sulfotransferase-1 by Wnt signaling triggers diffusion of Wnt-3a.
During metazoan development, Wnt molecules are secreted from Wnt-producing cells, diffuse to target cells, and determine cell fates; therefore, Wnt secretion is tightly regulated. However, the molecular mechanisms controlling Wnt diffusion are not fully elucidated. The specific chondroitin sulfate (CS) structure synthesized by chondroitin-4-O-sulfotransferase-1 (C4ST-1) binds to Wnt-3a with high affinity (Nadanaka, S., Ishida, M., Ikegami, M., and Kitagawa, H. (2008) J. Biol. Chem. 283, 27333-27343). In this study we tested whether Wnt signaling regulates sulfation patterns of cell-associated CS chains by suppressing expression of C4ST-1 to trigger release of Wnt molecules from Wnt-producing cells. C4ST-1 expression was dramatically reduced in L cells that stably expressed Wnt-3a (L-Wnt-3a cells) and had CS with low affinity for Wnt-3a. Forced expression of C4ST-1 in L-Wnt-3a cells inhibited diffusion of Wnt-3a due to structural alterations in CS chains mediated by C4ST-1. Furthermore, sustained Wnt signaling negatively regulated C4ST-1 expression in a cell-autonomous and non-cell autonomous fashion. These results demonstrated that C4ST-1 is a key downstream target of Wnt signaling that regulates Wnt diffusion from Wnt-producing cells.
Department of Biochemistry, Kobe Pharmaceutical University, Kobe 658-8558, Japan.
Satomi
S
Nadanaka
Hiroki
H
Kinouchi
Kayo
K
Taniguchi-Morita
Jun-ichi
J
Tamura
Hiroshi
H
Kitagawa
D000818:Animals; D002809:Chondroitin Sulfates / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D007739:L Cells; D051379:Mice; D015398:Signal Transduction / Q000502:physiology*; D015238:Sulfotransferases / Q000096:biosynthesis* / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D002809:Chondroitin Sulfates; D015238:Sulfotransferases