Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors.
Nkx6 transcription factors and Ptf1a function as antagonistic lineage determinants in multipotent pancreatic progenitors.
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DOI：
10.1016/j.devcel.2010.05.015
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发表时间：
2010-06-15
影响因子：
11.8
通讯作者：
Sander, Maike
中科院分区：
文献类型：
--
作者：
Schaffer, Ashleigh E.;Freude, Kristine K.;Nelson, Shelley B.;Sander, Maike
胰腺中多能祖细胞分化的分子机制几乎是未知的。在这里，我们表明胰腺前体细胞在内分泌和腺泡细胞谱系之间的早期命运选择受到转录因子Nkx6.1/Nkx6.2(NKX6)和Ptf1a之间的交叉抑制相互作用的限制。使用遗传功能丧失和功能获得的方法，我们证明了NKX6因子和Ptf1a分别是抑制替代谱系程序和指定祖细胞走向内分泌或腺泡命运所必需的且充分的。NKX6/Ptf1a开关仅在前体细胞仍具有多能性且可与细胞分化解偶联的关键能力窗口中运行。因此，NKX6和Ptf1a在多能祖细胞中的交叉拮抗作用控制着正常胰腺发育所需的内分泌和腺泡细胞新生之间的平衡。
The molecular mechanisms that underlie cell lineage diversification of multipotent progenitors in the pancreas are virtually unknown. Here, we show that the early fate choice of pancreatic progenitors between the endocrine and acinar cell lineage is restricted by cross-repressive interactions between the transcription factors Nkx6.1/Nkx6.2 (Nkx6) and Ptf1a. Using genetic loss- and gain-of-function approaches, we demonstrate that Nkx6 factors and Ptf1a are required and sufficient to repress the alternative lineage program and to specify progenitors toward an endocrine or acinar fate, respectively. The Nkx6/Ptf1a switch only operates during a critical competence window when progenitors are still multipotent and can be uncoupled from cell differentiation. Thus, cross-antagonism between Nkx6 and Ptf1a in multipotent progenitors governs the equilibrium between endocrine and acinar cell neogenesis required for normal pancreas development.
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