Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells.
Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells.
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DOI：
10.1053/j.gastro.2011.01.005
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发表时间：
2011-04
期刊：
影响因子：
29.4
通讯作者：
Radtke F
中科院分区：
文献类型：
--
作者：
Pellegrinet L;Rodilla V;Liu Z;Chen S;Koch U;Espinosa L;Kaestner KH;Kopan R;Lewis J;Radtke F
肠上皮内Notch信号的消融会导致增殖的隐窝祖细胞的损失，因为它们转化为有丝分裂后分泌细胞。我们的目的是确认 Notch 在干细胞 (SC) 中具有活性，研究肠道 SC 区室中 Notch 信号丢失的后果，并鉴定小鼠肠道中 Notch 的生理配体。此外，我们还研究了因Notch缺失而诱导杯状细胞分化是否需要转录因子Krüppel样因子4（Klf4）。携带Notch1激活报告基因的转基因小鼠被用于谱系追踪实验。在具有诱导型肠道特异性基因靶向 (Vil-Cre-ERT2) 的小鼠中评估了 Notch 配体 Jagged1 (Jag1)、Delta-like1 (Dll1)、Delta-like4 (Dll4) 和转录因子 Klf4 的体内功能。发现 Notch1 信号在肠道 SC 中被激活。尽管 Jag1 或 Dll4 的缺失不会干扰肠上皮，但 Dll1 的失活会导致杯状细胞数量适度增加，且不会对祖细胞增殖产生明显影响。然而，Dll1 和 Dll4 同时失活导致增殖祖细胞完全转化为有丝分裂后杯状细胞，同时伴有 SC（Olfm4+、Lgr5+ 和 Ascl2+）的损失。 Klf4 失活不会干扰成年野生型或 Notch 途径缺陷肠道中的杯状细胞分化。 SC 和祖细胞中的 Notch 信号传导由 Dll1 和 Dll4 配体激活，并且是维持肠祖细胞和 SC 所必需的。 Klf4 对于成年 Notch 缺陷小鼠肠道中的杯状细胞分化是必不可少的。
Ablation of Notch signaling within the intestinal epithelium results in loss of proliferating crypt progenitors, due to their conversion into post-mitotic secretory cells. We aimed to confirm that Notch was active in stem cells (SC), investigate consequences of loss of Notch signaling within the intestinal SC compartment, and identify the physiological ligands of Notch in mouse intestine. Furthermore, we investigated whether the induction of goblet cell differentiation that results from loss of Notch requires the transcription factor Krüppel-like factor 4 (Klf4). Trasgenic mice that carried a reporter of Notch1 activation were used for lineage tracing experiments. The in vivo functions of the Notch ligands Jagged1 (Jag1), Delta-like1 (Dll1), Delta-like4 (Dll4), and the transcription factor Klf4 were assessed in mice with inducible, gut-specific gene targeting (Vil-Cre-ERT2). Notch1 signaling was found to be activated in intestinal SC. Although deletion of Jag1 or Dll4 did not perturb the intestinal epithelium, inactivation of Dll1 resulted in a moderate increase in number of goblet cells without noticeable effects of progenitor proliferation. However, simultaneous inactivation of Dll1 and Dll4 resulted in the complete conversion of proliferating progenitors into post-mitotic goblet cells, concomitant with loss of SC (Olfm4+, Lgr5+ and Ascl2+). Klf4 inactivation did not interfere with goblet cell differentiation in adult wild-type or in Notch pathway-deficient gut. Notch signaling in SC and progenitors is activated by Dll1 and Dll4 ligands and is required for maintenance of intestinal progenitor and SC. Klf4 is dispensable for goblet cell differentiation in intestines of adult Notch-deficient mice.
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DOI：
10.1084/jem.20061442
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Besseyrias V;Fiorini E;Strobl LJ;Zimber-Strobl U;Dumortier A;Koch U;Arcangeli ML;Ezine S;Macdonald HR;Radtke F
通讯作者：
Radtke F
影响因子：
2.7
作者：
Ghaleb AM;McConnell BB;Kaestner KH;Yang VW
通讯作者：
Yang VW
影响因子：
11.5
作者：
Patel, Nilay S.;Dobbie, Michael S.;Harris, Adrian L.
通讯作者：
Harris, Adrian L.
影响因子：
20.3
作者：
Mancini, SJC;Mantei, N;Radtke, F
通讯作者：
Radtke, F
DOI：
10.1111/j.1365-2184.1974.tb00907.x
发表时间：
1974-01-01
期刊：
CELL AND TISSUE KINETICS
影响因子：
--
作者：
POTTEN, CS;KOVACS, L;HAMILTON, E
通讯作者：
HAMILTON, E