Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas.
Ongoing Notch signaling maintains phenotypic fidelity in the adult exocrine pancreas.
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DOI：
10.1016/j.ydbio.2011.11.010
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发表时间：
2012-02-01
影响因子：
2.7
通讯作者：
Murtaugh LC
中科院分区：
文献类型：
--
作者：
Kopinke D;Brailsford M;Pan FC;Magnuson MA;Wright CV;Murtaugh LC
Notch信号通路调节胰腺的胚胎发育，抑制祖细胞分化为外分泌腺泡细胞和内分泌胰岛细胞。成人胰腺似乎缺乏祖细胞，其成熟的细胞类型由预先存在的分化细胞的增殖维持。尽管如此，Notch在成体导管和终末导管/中央腺泡细胞(CACs)中仍然活跃，其功能尚不清楚。我们之前建立的小鼠可以通过表达Cre重组酶来标记和操纵表达Notch靶基因Hes1的细胞，并证明Hes1+CACs在未损伤的胰腺中不表现为腺泡或胰岛前体细胞，或者在胰管结扎后不作为胰岛前体细胞。在目前的研究中，我们通过删除Notch的转录因子伙伴Rbpj，特别是在Hes1+细胞中，评估了Notch信号在成年胰腺中的功能。我们发现，Rbpj的丢失耗尽了表达Hes1的CACs的胰腺，取消了它们对更近端导管结构的生长和动态平衡的持续贡献。Rbpj缺失后，CACs迅速转化为腺泡细胞，提示结构性Notch活性抑制了CACs的腺泡分化潜能。总之，我们的数据提供了控制成人胰腺细胞命运相互转换的内源性遗传程序的直接证据。
The Notch signaling pathway regulates embryonic development of the pancreas, inhibiting progenitor differentiation into exocrine acinar and endocrine islet cells. The adult pancreas appears to lack progenitor cells, and its mature cell types are maintained by the proliferation of pre-existing differentiated cells. Nonetheless, Notch remains active in adult duct and terminal duct/centroacinar cells (CACs), in which its function is unknown. We previously developed mice in which cells expressing the Notch target gene Hes1 can be labeled and manipulated, by expression of Cre recombinase, and demonstrated that Hes1+ CACs do not behave as acinar or islet progenitors in the uninjured pancreas, or as islet progenitors after pancreatic duct ligation. In the current study, we assessed the function of Notch signaling in the adult pancreas by deleting the transcription factor partner of Notch, Rbpj, specifically in Hes1+ cells. We find that loss of Rbpj depletes the pancreas of Hes1-expressing CACs, abrogating their ongoing contribution to growth and homeostasis of more proximal duct structures. Upon Rbpj deletion, CACs undergo a rapid transformation into acinar cells, suggesting that constitutive Notch activity suppresses the acinar differentiation potential of CACs. Together, our data provide direct evidence of an endogenous genetic program to control interconversion of cell fates in the adult pancreas.
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影响因子：
9.8
作者：
Brennand K;Huangfu D;Melton D
通讯作者：
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影响因子：
2.6
作者：
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DOI：
10.1073/pnas.0810111105
发表时间：
2008-12-02
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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