Jiang Dan, Li Pengyue, Lu Yi, Tao Jiaxin, Hao Xue, Wang Xiaodong, Wu Wei, Xu Jinjin, Zhang Haoen, Li Xiaoyu, Chen Yixing, Jin Yunyun, Zhang Lei
The Department of Urology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, 200233, China.
Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Minghang, Shanghai, 200240, China.
Nat Commun. 2025 Jan 10;16(1):570. doi: 10.1038/s41467-024-55255-1.
Balanced self-renewal and differentiation of stem cells are crucial for maintaining tissue homeostasis, but the underlying mechanisms of this process remain poorly understood. Here, from an RNA interference (RNAi) screen in adult Drosophila intestinal stem cells (ISCs), we identify a factor, Pax, which is orthologous to mammalian PXN, coordinates the proliferation and differentiation of ISCs during both normal homeostasis and injury-induced midgut regeneration in Drosophila. Loss of Pax promotes ISC proliferation while suppressing its differentiation into absorptive enterocytes (ECs). Mechanistically, our findings demonstrate that Pax is a conserved target gene of the Hippo signaling pathway in both Drosophila and mammals. Subsequent investigations have revealed Pax interacts with Yki and enhances its cytoplasmic localization, thereby establishing a feedback regulatory mechanism that attenuates Yki activity and ultimately inhibits ISCs proliferation. Additionally, Pax induces the differentiation of ISCs into ECs by activating Notch expression, thus facilitating the differentiation process. Overall, our study highlights Pax as a pivotal component of the Hippo and Notch pathways in regulating midgut homeostasis, shedding light on this growth-related pathway in tissue maintenance and intestinal function.
干细胞的平衡自我更新和分化对于维持组织稳态至关重要，但这一过程的潜在机制仍知之甚少。在这里，通过对成年果蝇肠道干细胞（ISC）进行RNA干扰（RNAi）筛选，我们鉴定出一个与哺乳动物PXN直系同源的因子Pax，它在果蝇正常稳态和损伤诱导的中肠再生过程中协调ISC的增殖和分化。Pax缺失促进ISC增殖，同时抑制其分化为吸收性肠上皮细胞（EC）。从机制上讲，我们的研究结果表明，Pax是果蝇和哺乳动物中Hippo信号通路的保守靶基因。随后的研究表明，Pax与Yki相互作用并增强其细胞质定位，从而建立一种反馈调节机制，减弱Yki活性并最终抑制ISC增殖。此外，Pax通过激活Notch表达诱导ISC分化为EC，从而促进分化过程。总体而言，我们的研究强调Pax是Hippo和Notch通路调节中肠稳态的关键组成部分，为这一与生长相关的通路在组织维持和肠道功能方面提供了新的认识。
