Tian Hua, Biehs Brian, Chiu Cecilia, Siebel Christian W, Wu Yan, Costa Mike, de Sauvage Frederic J, Klein Ophir D
Departments of Orofacial Sciences and Pediatrics, Institute of Human Genetics and Program in Craniofacial Biology, UCSF, 513 Parnassus Avenue, San Francisco, CA 94143-0442, USA.
Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Cell Rep. 2015 Apr 7;11(1):33-42. doi: 10.1016/j.celrep.2015.03.007. Epub 2015 Mar 26.
Proper organ homeostasis requires tight control of adult stem cells and differentiation through the integration of multiple inputs. In the mouse small intestine, Notch and Wnt signaling are required both for stem cell maintenance and for a proper balance of differentiation between secretory and absorptive cell lineages. In the absence of Notch signaling, stem cells preferentially generate secretory cells at the expense of absorptive cells. Here, we use function-blocking antibodies against Notch receptors to demonstrate that Notch blockade perturbs intestinal stem cell function by causing a derepression of the Wnt signaling pathway, leading to misexpression of prosecretory genes. Importantly, attenuation of the Wnt pathway rescued the phenotype associated with Notch blockade. These studies bring to light a negative regulatory mechanism that maintains stem cell activity and balanced differentiation, and we propose that the interaction between Wnt and Notch signaling described here represents a common theme in adult stem cell biology.
适当的器官内环境稳定需要通过整合多种输入信号来严格控制成体干细胞及其分化。在小鼠小肠中，Notch信号和Wnt信号对于干细胞维持以及分泌细胞谱系和吸收细胞谱系之间适当的分化平衡都是必需的。在没有Notch信号的情况下，干细胞优先生成分泌细胞，而以吸收细胞为代价。在这里，我们使用针对Notch受体的功能阻断抗体来证明，Notch阻断通过导致Wnt信号通路的去抑制来扰乱肠道干细胞功能，从而导致促分泌基因的错误表达。重要的是，Wnt通路的减弱挽救了与Notch阻断相关的表型。这些研究揭示了一种维持干细胞活性和平衡分化的负调控机制，并且我们提出这里描述的Wnt和Notch信号之间的相互作用代表了成体干细胞生物学中的一个共同主题。
