Genetic Evidence That Intestinal Notch Functions Vary Regionally and Operate through a Common Mechanism of Math1 Repression
Genetic Evidence That Intestinal Notch Functions Vary Regionally and Operate through a Common Mechanism of Math1 Repression
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DOI：
10.1074/jbc.m110.188797
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发表时间：
2011-04-01
影响因子：
4.8
通讯作者：
Shivdasani, Ramesh A.
中科院分区：
文献类型：
--
作者：
Kim, Tae-Hee;Shivdasani, Ramesh A.
Notch信号在许多位点都是活跃的，其多样的活动必须需要组织特异性中介，这在很大程度上是未知的。在肠上皮中，Notch促进隐窝细胞增殖并抑制杯状细胞分化。药理学研究表明，后一种作用是通过转录因子Math 1/Atoh 1发生的，该因子指定所有肠道分泌细胞。我们用小鼠突变体测试了这一假设。Notch效应子RBP-J κ的遗传缺失单独增加了所有肠分泌谱系，近端和远端肠段之间存在差异。在RBP-J κ（F1/F1）; Math 1（F1/F1）; Villin-Cre（（ER-T2））小鼠中，在不存在Math 1的情况下，在RBP-J κ损失的情况下观察到的这种分泌细胞过量被阻断。这两种因子的缺失也恢复了祖细胞复制，证明Math 1在分泌细胞分化和隐窝细胞增殖中对Notch信号传导是上位的。研究Math 1下游的机制，我们发现已知Notch效应蛋白Hes 1的表达在RBP-J κ（-/-）小鼠中可预测地丢失，但令人惊讶地在RBP-J κ; Math 1复合条件突变体中恢复。此外，细胞周期抑制剂p27（Kip 1）和p57（Kip 2）分别在RBP-J κ缺陷小鼠的十二指肠和回肠隐窝中选择性过表达。在没有Math 1的情况下，这些产品的区域激活被完全废除。因此，所有的肠道Notch效应都通过组织限制性因子Math 1，Math 1通过区域不同的机制促进分泌分化和细胞周期退出。我们的数据进一步表明，除了传输Notch信号，转录因子Hes 1的下游Math 1的行为，以调节细胞周期抑制剂的表达和肠隐窝细胞复制。
Notch signaling is active in many sites, and its diverse activities must require tissue-specific intermediaries, which are largely unknown. In the intestinal epithelium, Notch promotes crypt cell proliferation and inhibits goblet cell differentiation. Pharmacologic studies suggest that the latter effect occurs through the transcription factor Math1/Atoh1, which specifies all intestinal secretory cells. We tested this hypothesis using mouse mutants. Genetic loss of the Notch effector RBP-J kappa alone increases all intestinal secretory lineages, with variation between proximal and distal gut segments. This secretory cell excess observed with RBP-J kappa loss was blocked in the absence of Math1 in RBP-J kappa(Fl/Fl); Math1(Fl/Fl); Villin-Cre((ER-T2)) mice. Loss of both factors also restored progenitor replication, proving that Math1 is epistatic to Notch signaling in both secretory cell differentiation and crypt cell proliferation. Investigating mechanisms downstream of Math1, we found that expression of the known Notch effector protein Hes1 was predictably lost in RBP-J kappa(-/-) mice but surprisingly recovered in RBP-J kappa;Math1 compound conditional mutants. Furthermore, the cell cycle inhibitors p27(Kip1) and p57(Kip2) were selectively overexpressed in duodenal and ileal crypts, respectively, in RBP-J kappa-deficient mice. Regional activation of these products was completely abrogated in the absence of Math1. Thus, all intestinal Notch effects channel through the tissue-restricted factor Math1, which promotes secretory differentiation and cell cycle exit by regionally distinct mechanisms. Our data further suggest that, besides transmitting Notch signals, the transcription factor Hes1 acts downstream of Math1 to regulate expression of cell cycle inhibitors and intestinal crypt cell replication.