NOTCH activity differentially affects alternative cell fate acquisition and maintenance.
NOTCH activity differentially affects alternative cell fate acquisition and maintenance.
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DOI：
10.7554/elife.33318
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发表时间：
2018-03-26
期刊：
影响因子：
7.7
通讯作者：
Rizzoti K
中科院分区：
文献类型：
--
作者：
Cheung L;Le Tissier P;Goldsmith SG;Treier M;Lovell-Badge R;Rizzoti K
垂体是一个重要的内分泌腺，调节多种过程。内分泌细胞的再生是治疗的兴趣，最近的研究是有希望的，但内分泌细胞的命运收购机制需要更好地表征。NOTCH通路在垂体发育过程中非常重要。在这里，我们进一步验证了它在小鼠垂体中的作用，揭示了谱系内和谱系之间的差异敏感性。在祖细胞中，NOTCH激活阻断细胞命运获取，具有时间依赖性调节。在分化细胞中，POU 1F 1谱系对激活的反应减弱，细胞命运规范明显正常，而POMC细胞保持敏感。Pou 1f 1-Cre; Rbpjfl/fl小鼠中没有明显缺陷进一步表明NOTCH信号传导在POU 1F 1细胞命运获得中没有直接作用。相反，在POMC谱系中，NICD表达诱导向祖细胞样状态的回归，表明NOTCH途径特异性阻断POMC细胞分化。这些结果对脑垂体的发育、可塑性和再生具有重要意义。NOTCH信号在胚胎小鼠垂体的不同细胞谱系中的激活揭示了意想不到的差异敏感性，并且这因此揭示了内分泌谱系发育和可塑性的新方面。
The pituitary is an essential endocrine gland regulating multiple processes. Regeneration of endocrine cells is of therapeutic interest and recent studies are promising, but mechanisms of endocrine cell fate acquisition need to be better characterised. The NOTCH pathway is important during pituitary development. Here, we further characterise its role in the murine pituitary, revealing differential sensitivity within and between lineages. In progenitors, NOTCH activation blocks cell fate acquisition, with time-dependant modulation. In differentiating cells, response to activation is blunted in the POU1F1 lineage, with apparently normal cell fate specification, while POMC cells remain sensitive. Absence of apparent defects in Pou1f1-Cre; Rbpjfl/fl mice further suggests no direct role for NOTCH signalling in POU1F1 cell fate acquisition. In contrast, in the POMC lineage, NICD expression induces a regression towards a progenitor-like state, suggesting that the NOTCH pathway specifically blocks POMC cell differentiation. These results have implications for pituitary development, plasticity and regeneration. Activation of NOTCH signalling in different cell lineages of the embryonic murine pituitary uncovers an unexpected differential sensitivity, and this consequently reveals new aspects of endocrine lineages development and plasticity.