Delta1 expression, cell cycle exit, and commitment to a specific secretory fate coincide within a few hours in the mouse intestinal stem cell system.
Delta1 expression, cell cycle exit, and commitment to a specific secretory fate coincide within a few hours in the mouse intestinal stem cell system.
复制标题
DOI：
10.1371/journal.pone.0024484
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Lewis J
中科院分区：
文献类型：
--
作者：
Stamataki D;Holder M;Hodgetts C;Jeffery R;Nye E;Spencer-Dene B;Winton DJ;Lewis J
小肠的干细胞是多能性的：它们通过过渡放大细胞分裂产生大量的柱状吸收细胞，其中混合有数量少得多的三种不同类型的分泌细胞-分泌粘液的杯状细胞，分泌粘液的肠内分泌细胞和分泌杀真菌剂的潘氏细胞。Notch信号被认为控制了分泌的命运，但是为什么分泌细胞在群体中占如此小的比例，以及分泌细胞类型的多样性是如何产生的？使用小鼠作为我们的模式生物，我们发现分泌细胞，只有分泌细胞，通过一个阶段的Notch配体Delta 1（Dll 1）的强表达。这种Dll 1表达的开始与进一步细胞分裂的阻断相一致，并且在比细胞周期时间短得多的时间内表达Neurog 3-肠内分泌命运的标志物-或Gfi 1-杯状或潘氏细胞命运的标志物。通过条件性敲除Dll 1，我们证实Delta-Notch信号通过侧向抑制控制分泌承诺。我们推断，细胞停止分裂，因为他们成为致力于分泌的命运，而他们的邻居继续分裂，解释了最终过量的吸收分泌细胞。我们的数据排除了细胞首先致力于分泌，然后通过随后的细胞分裂多样化的方案。一个简单的数学模型显示，相反，Notch信号可以同时管理的承诺是分泌和分泌分化的替代模式之间的选择。
The stem cells of the small intestine are multipotent: they give rise, via transit-amplifying cell divisions, to large numbers of columnar absorptive cells mixed with much smaller numbers of three different classes of secretory cells - mucus-secreting goblet cells, hormone-secreting enteroendocrine cells, and bactericide-secreting Paneth cells. Notch signaling is known to control commitment to a secretory fate, but why are the secretory cells such a small fraction of the population, and how does the diversity of secretory cell types arise? Using the mouse as our model organism, we find that secretory cells, and only secretory cells, pass through a phase of strong expression of the Notch ligand Delta1 (Dll1). Onset of this Dll1 expression coincides with a block to further cell division and is followed in much less than a cell cycle time by expression of Neurog3 – a marker of enteroendocrine fate – or Gfi1 – a marker of goblet or Paneth cell fate. By conditional knock-out of Dll1, we confirm that Delta-Notch signaling controls secretory commitment through lateral inhibition. We infer that cells stop dividing as they become committed to a secretory fate, while their neighbors continue dividing, explaining the final excess of absorptive over secretory cells. Our data rule out schemes in which cells first become committed to be secretory, and then diversify through subsequent cell divisions. A simple mathematical model shows how, instead, Notch signaling may simultaneously govern the commitment to be secretory and the choice between alternative modes of secretory differentiation.
登录
查看更多内容
影响因子：
11.4
作者：
Jenny, M;Uhl, C;Gradwohl, G
通讯作者：
Gradwohl, G
影响因子：
9.8
作者：
Bossuyt W;Kazanjian A;De Geest N;Van Kelst S;De Hertogh G;Geboes K;Boivin GP;Luciani J;Fuks F;Chuah M;VandenDriessche T;Marynen P;Cools J;Shroyer NF;Hassan BA
通讯作者：
Hassan BA
影响因子：
4.6
作者：
Brooker, R;Hozumi, K;Lewis, J
通讯作者：
Lewis, J
影响因子：
2
作者：
Collier, JR;Monk, NAM;Lewis, JH
通讯作者：
Lewis, JH
DOI：
10.1073/pnas.97.22.11692
发表时间：
2000-10-24
影响因子：
11.1
作者：
Eddison, M;Le Roux, I;Lewis, J
通讯作者：
Lewis, J