Institut Curie, PSL Research University, CNRS UMR 3215, INSERM U934, Stem Cells and Tissue Homeostasis group, Sorbonne Université, UPMC Univ Paris 6, Paris, France.
Discngine, Paris, France.
PLoS Genet. 2018 Nov 19;14(11):e1007773. doi: 10.1371/journal.pgen.1007773. eCollection 2018 Nov.
Precise regulation of stem cell self-renewal and differentiation properties is essential for tissue homeostasis. Using the adult Drosophila intestine to study molecular mechanisms controlling stem cell properties, we identify the gene split-ends (spen) in a genetic screen as a novel regulator of intestinal stem cell fate (ISC). Spen family genes encode conserved RNA recognition motif-containing proteins that are reported to have roles in RNA splicing and transcriptional regulation. We demonstrate that spen acts at multiple points in the ISC lineage with an ISC-intrinsic function in controlling early commitment events of the stem cells and functions in terminally differentiated cells to further limit the proliferation of ISCs. Using two-color cell sorting of stem cells and their daughters, we characterize spen-dependent changes in RNA abundance and exon usage and find potential key regulators downstream of spen. Our work identifies spen as an important regulator of adult stem cells in the Drosophila intestine, provides new insight to Spen-family protein functions, and may also shed light on Spen's mode of action in other developmental contexts.
精确调控干细胞的自我更新和分化特性对于组织稳态至关重要。我们利用成年果蝇肠道来研究调控干细胞特性的分子机制，在一个遗传筛选中发现基因 split-ends（spen）是肠道干细胞命运（ISC）的一个新的调控因子。Spen 家族基因编码含有保守 RNA 识别模体的蛋白，据报道它们在 RNA 剪接和转录调控中发挥作用。我们证明 spen 在 ISC 谱系中多个位置发挥作用，在控制干细胞的早期定向事件中具有 ISC 内在功能，并在终末分化细胞中发挥作用，进一步限制 ISC 的增殖。通过对干细胞及其后代的双色细胞分选，我们描述了 spen 依赖性的 RNA 丰度和外显子使用变化，并发现了 spen 下游的潜在关键调控因子。我们的工作鉴定了 spen 作为果蝇肠道中成年干细胞的重要调控因子，为 Spen 家族蛋白功能提供了新的见解，并且可能也揭示了 Spen 在其他发育背景中的作用模式。
