| セッション情報 |
パネルディスカッション5.
粘膜再生からみた炎症性腸疾患
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| タイトル |
PD5-01 Systemically expressed Wnt inhibitors/agonist as probes for Wnt signaling functions in the adult intestine
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| 演者 |
大谷顕史（Department of MedicineStanford University） |
| 共同演者 |
Mark Lee（Department of MedicineStanford University）, Calvin Kuo（Department of MedicineStanford University） |
| 抄録 |
The intestinal epithelium undergoes rapid and perpetual self－renewalalong the crypt“villus axisand Wnt signaling persists as a key regtilatorof homeostasis in adult self－renewing tissue． To explore roles of Wnt sig－naling on the adult intestinal homeostasiswe have generated a panel ofrecombinant adenoviruses （Ad） which perrnit systemic expression of se－creted Wnt inhibitors／agonist following intravenous administration inadult mice． We previously reported the phenotype of Ad Dickkopf－1（Dlcl［1）which blocks intestinal crypt proliferation and Wnt一一dependentgene expression in vivo （KuhnertPNAS 2004） ． An adenovirus express－ing a Wnt inhibitor comprising the Frizzled8 cysteine－rich domain fusedto the mouse Fc domain （Fz8－Fc） also signhicantly compromises intesti－nal epithelial homeostasiswith more extensive suppression of intestinalcrypt proliferation and more rapid lethality than Ad Dkkl． HoweverAdWIFI and Ad RykN－Fc （extracellular domain of Ryk） do not exhibit thisintestinal toxicity． Co！1verselyAd R－Spondi皿1 （RSpo 1）strongly in－creases intestinal crypt proliferation ； the Wnt agonist RSpo l is a se－creted glycoprotein with no homology with Wnt but which synergizeswith Wnt to activ訊teβ一catenin－dependent signa血g． These results indi・cate that extracellular Wnt signaling actively maintains the robust andhomeostatic proliferation of adult small intestine and colon． Furtherdif－ferences in the phenotypes observed with each Wnt inhibitors／agonistadenovirus wM serve as powerful probes into the tissue－specific re－quirements for Wnt signaling in normal adult physiology． |
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