Lin-28 promotes symmetric stem cell division and drives adaptive growth in the adult Drosophila intestine
Lin-28 promotes symmetric stem cell division and drives adaptive growth in the adult Drosophila intestine
复制标题
DOI：
10.1242/dev.127951
复制
发表时间：
2015-10-15
期刊：
影响因子：
4.6
通讯作者：
Sokol, Nicholas
中科院分区：
文献类型：
--
作者：
Chen, Ching-Huan;Luhur, Arthur;Sokol, Nicholas
干细胞在不对称和对称分裂之间转换，随着组织在发育过程中的生长和对环境变化的反应而在数量上扩大。控制这种开关的干细胞内在蛋白质在很大程度上是未知的，但一个候选者是Lin-28多能性因子。Lin-28是一种保守的RNA结合蛋白，在大多数动物从胚胎发育到成年时下调，在成体干细胞群体中持续存在。它在这些细胞中的功能以前没有被表征。在这里，我们报告说，林-28是高度富集在果蝇肠道的成体肠干细胞。Lin-28无效突变体是纯合的活的，但在该细胞群体中显示出缺陷，其不能经历特征性的食物触发的数量扩增，并且具有降低的对称分裂速率以及降低的胰岛素信号传导。Lin-28结合mRNA的免疫沉淀鉴定了胰岛素样受体（InR），其强制表达完全挽救了lin-28相关的肠干细胞数量和分裂模式缺陷。此外，lin-28的这种干细胞活性不依赖于一种公知的lin-28靶标，即microRNA let-7，其在肠上皮中的表达有限。这些结果将Lin-28鉴定为干细胞内在因子，其增强肠祖细胞中的胰岛素信号传导并促进其响应于营养物的对称分裂，定义了Lin-28控制成体干细胞分裂模式的机制，该分裂模式是组织稳态和再生的基础。
Stem cells switch between asymmetric and symmetric division to expand in number as tissues grow during development and in response to environmental changes. The stem cell intrinsic proteins controlling this switch are largely unknown, but one candidate is the Lin-28 pluripotency factor. A conserved RNA-binding protein that is downregulated in most animals as they develop from embryos to adults, Lin-28 persists in populations of adult stem cells. Its function in these cells has not been previously characterized. Here, we report that Lin-28 is highly enriched in adult intestinal stem cells in the Drosophila intestine. lin-28 null mutants are homozygous viable but display defects in this population of cells, which fail to undergo a characteristic food-triggered expansion in number and have reduced rates of symmetric division as well as reduced insulin signaling. Immunoprecipitation of Lin-28-bound mRNAs identified Insulin-like Receptor (InR), forced expression of which completely rescues lin-28-associated defects in intestinal stem cell number and division pattern. Furthermore, this stem cell activity of lin-28 is independent of one well-known lin-28 target, the microRNA let-7, which has limited expression in the intestinal epithelium. These results identify Lin-28 as a stem cell intrinsic factor that boosts insulin signaling in intestinal progenitor cells and promotes their symmetric division in response to nutrients, defining a mechanism through which Lin-28 controls the adult stem cell division patterns that underlie tissue homeostasis and regeneration.