Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Development. 2010 Dec;137(24):4135-45. doi: 10.1242/dev.060483.
Identification of the signaling pathways that control the proliferation of stem cells (SCs), and whether they act in a cell or non-cell autonomous manner, is key to our understanding of tissue homeostasis and cancer. In the adult Drosophila midgut, the Jun N-Terminal Kinase (JNK) pathway is activated in damaged enterocyte cells (ECs) following injury. This leads to the production of Upd cytokines from ECs, which in turn activate the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway in Intestinal SCs (ISCs), stimulating their proliferation. In addition, the Hippo pathway has been recently implicated in the regulation of Upd production from the ECs. Here, we show that the Hippo pathway target, Yorkie (Yki), also plays a crucial and cell-autonomous role in ISCs. Activation of Yki in ISCs is sufficient to increase ISC proliferation, a process involving Yki target genes that promote division, survival and the Upd cytokines. We further show that prior to injury, Yki activity is constitutively repressed by the upstream Hippo pathway members Fat and Dachsous (Ds). These findings demonstrate a cell-autonomous role for the Hippo pathway in SCs, and have implications for understanding the role of this pathway in tumorigenesis and cancer stem cells.
鉴定控制干细胞（SCs）增殖的信号通路，以及它们是否以细胞自主或非细胞自主的方式发挥作用，是我们理解组织内稳态和癌症的关键。在成年果蝇中肠中，JNK 途径在损伤后受损的肠细胞（ECs）中被激活。这导致 EC 产生 Upd 细胞因子，反过来又在肠干细胞（ISCs）中的 Janus 激酶（JAK）/信号转导和转录激活因子（STAT）途径中被激活，刺激其增殖。此外，Hippo 途径最近也被牵涉到 EC 中 Upd 产生的调节中。在这里，我们表明 Hippo 途径的靶标 Yorkie（Yki）也在 ISCs 中发挥着至关重要的、细胞自主的作用。Yki 在 ISCs 中的激活足以增加 ISC 的增殖，这一过程涉及到促进分裂、存活和 Upd 细胞因子的 Yki 靶基因。我们进一步表明，在损伤之前，上游 Hippo 途径成员 Fat 和 Dachsous（Ds）就一直抑制 Yki 的活性。这些发现证明了 Hippo 途径在 SCs 中的细胞自主作用，并对理解该途径在肿瘤发生和癌症干细胞中的作用具有重要意义。
