Wang Chenhui, Guo Xingting, Dou Kun, Chen Hongyan, Xi Rongwen
National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China
Development. 2015 Oct 1;142(19):3321-31. doi: 10.1242/dev.123208. Epub 2015 Aug 20.
In adult Drosophila midgut, intestinal stem cells (ISCs) periodically produce progenitor cells that undergo a binary fate choice determined primarily by the levels of Notch activity that they receive, before terminally differentiating into enterocytes (ECs) or enteroendocrine (EE) cells. Here we identified Ttk69, a BTB domain-containing transcriptional repressor, as a master repressor of EE cell specification in the ISC lineages. Depletion of ttk69 in progenitor cells induced ISC proliferation and caused all committed progenitor cells to adopt EE fate, leading to the production of supernumerary EE cells in the intestinal epithelium. Conversely, forced expression of Ttk69 in progenitor cells was sufficient to prevent EE cell specification. The expression of Ttk69 was not regulated by Notch signaling, and forced activation of Notch, which is sufficient to induce EC specification of normal progenitor cells, failed to prevent EE cell specification of Ttk69-depleted progenitors. Loss of Ttk69 led to derepression of the acheate-scute complex (AS-C) genes scute and asense, which then induced prospero expression to promote EE cell specification. These studies suggest that Ttk69 functions in parallel with Notch signaling and acts as a master repressor of EE cell specification in Drosophila ISC lineages primarily by suppressing AS-C genes.
在成年果蝇的中肠中，肠道干细胞（ISC）会周期性地产生祖细胞，这些祖细胞在最终分化为肠细胞（EC）或肠内分泌（EE）细胞之前，会经历主要由它们所接收的Notch活性水平决定的二元命运选择。在这里，我们鉴定出Ttk69，一种含BTB结构域的转录抑制因子，是ISC谱系中EE细胞特化的主要抑制因子。祖细胞中ttk69的缺失会诱导ISC增殖，并导致所有已分化的祖细胞都采用EE命运，从而在肠上皮中产生多余的EE细胞。相反，在祖细胞中强制表达Ttk69足以阻止EE细胞特化。Ttk69的表达不受Notch信号通路的调节，并且强制激活Notch（这足以诱导正常祖细胞的EC特化）并不能阻止Ttk69缺失的祖细胞的EE细胞特化。Ttk69的缺失导致achaete - scute复合体（AS - C）基因scute和asense的去抑制，进而诱导prospero表达以促进EE细胞特化。这些研究表明，Ttk69与Notch信号通路并行发挥作用，并且主要通过抑制AS - C基因，作为果蝇ISC谱系中EE细胞特化的主要抑制因子。
