Complement C1q Activates Canonical Wnt Signaling and Promotes Aging-Related Phenotypes

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• 作者：Atsuhiko  ; T. Naito¹ ; ³ ; Tomokazu Sumida⁴ ; Seitaro Nomura⁴ ; Mei-Lan Liu⁴ ; Tomoaki Higo¹ ; Akito Nakagawa¹ ; Katsuki Okada¹ ; Taku Sakai¹ ; Akihito Hashimoto¹ ; Yurina Hara¹ ; Ippei Shimizu⁴ ; Weidong Zhu⁴ ; Haruhiro Toko⁴ ; Akemi Katada⁴ ; Hiroshi Akazawa¹ ; ³ ; Toru Oka¹ ; ³ ; Jong-Kook Lee¹ ; ³ ; Tohru Minamino⁴ ; Toshio Nagai⁴ ; Kenneth Walsh⁵ ; Akira Kikuchi² ; Misako Matsumoto⁶ ; Marina Botto⁷ ; Ichiro Shiojima¹ ; ³ ; Issei Komuro¹ ; ³ ; ⁴ ; ^{komuro-tky@umin.ac.jp}
• 刊名：Cell
• 出版年：2012
• 期刊代码：50_00928674
• 类别：med
• 出版时间：8 June, 2012
• 卷：149
• 期：6
• 页码：1298-1313
• 文件大小：2063 K

摘要

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Summary

Wnt signaling plays critical roles in development of various organs and pathogenesis of many diseases, and augmented Wnt signaling has recently been implicated in mammalian aging and aging-related phenotypes. We here report that complement C1q activates canonical Wnt signaling and promotes aging-associated decline in tissue regeneration. Serum C1q concentration is increased with aging, and Wnt signaling activity is augmented during aging in the serum and in multiple tissues of wild-type mice, but not in those of C1qa-deficient mice. C1q activates canonical Wnt signaling by binding to Frizzled receptors and subsequently inducing C1s-dependent cleavage of the ectodomain of Wnt coreceptor low-density lipoprotein receptor-related protein 6. Skeletal muscle regeneration in young mice is inhibited by exogenous C1q treatment, whereas aging-associated impairment of muscle regeneration is restored by C1s inhibition or C1qa gene disruption. Our findings therefore suggest the unexpected role of complement C1q in Wnt signal transduction and modulation of mammalian aging.