Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, 94305, USA.
Molecular and Computational Biology Department, University of Southern California, Los Angeles, California, 90087, USA.
Sci Rep. 2018 Nov 30;8(1):17506. doi: 10.1038/s41598-018-34562-w.
Regulation of the Wnt pathway in stem cells and primary tissues is still poorly understood. Here we report that Usp16, a negative regulator of Bmi1/PRC1 function, modulates the Wnt pathway in mammary epithelia, primary human fibroblasts and MEFs, affecting their expansion and self-renewal potential. In mammary glands, reduced levels of Usp16 increase tissue responsiveness to Wnt, resulting in upregulation of the downstream Wnt target Axin2, expansion of the basal compartment and increased in vitro and in vivo epithelial regeneration. Usp16 regulation of the Wnt pathway in mouse and human tissues is at least in part mediated by activation of Cdkn2a, a regulator of senescence. At the molecular level, Usp16 affects Rspo-mediated phosphorylation of LRP6. In Down's Syndrome (DS), triplication of Usp16 dampens the activation of the Wnt pathway. Usp16 copy number normalization restores normal Wnt activation in Ts65Dn mice models. Genetic upregulation of the Wnt pathway in Ts65Dn mice rescues the proliferation defect observed in mammary epithelial cells. All together, these findings link important stem cell regulators like Bmi1/Usp16 and Cdkn2a to Wnt signaling, and have implications for designing therapies for conditions, like DS, aging or degenerative diseases, where the Wnt pathway is hampered.
Wnt 通路在干细胞和原代组织中的调控仍知之甚少。本文报道称，Bmi1/PRC1 功能的负调控因子 Usp16 可调节乳腺上皮细胞、原代人成纤维细胞和 MEFs 中的 Wnt 通路，影响其扩增和自我更新能力。在乳腺组织中，Usp16 水平降低会增加组织对 Wnt 的反应性，导致下游 Wnt 靶标 Axin2 的上调、基底细胞的扩增以及体外和体内上皮再生能力的增强。Usp16 对小鼠和人组织中 Wnt 通路的调控至少部分是通过激活衰老调节剂 Cdkn2a 介导的。在唐氏综合征（Down's Syndrome，DS）中，Usp16 的三倍体抑制了 Wnt 通路的激活。Ts65Dn 小鼠模型中 Usp16 拷贝数的正常化恢复了正常的 Wnt 激活。在 Ts65Dn 小鼠中上调 Wnt 通路的遗传表达可挽救乳腺上皮细胞中观察到的增殖缺陷。综上所述，这些发现将 Bmi1/Usp16 和 Cdkn2a 等重要的干细胞调控因子与 Wnt 信号联系起来，并为设计针对 Wnt 通路受损的疾病的治疗方法提供了依据，如 DS、衰老或退行性疾病。
