Department of Human Genetics, University of Michigan, Ann Arbor, United States.
Centre for Discovery Brain Science, Integrative Physiology, Edinburgh, United Kingdom.
Elife. 2018 Mar 26;7:e33318. doi: 10.7554/eLife.33318.
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 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.
垂体是调节多种过程的重要内分泌腺。内分泌细胞的再生具有治疗意义，最近的研究有很大的希望，但需要更好地描述内分泌细胞命运获得的机制。NOTCH 途径在垂体发育过程中很重要。在这里，我们进一步描述了它在小鼠垂体中的作用，揭示了在谱系内和谱系之间的不同敏感性。在祖细胞中，NOTCH 激活阻止细胞命运获得，且具有时间依赖性的调节。在分化细胞中，激活反应在 POU1F1 谱系中减弱，表现为正常的细胞命运特化，而 POMC 细胞仍然敏感。在 小鼠中没有明显缺陷的存在进一步表明 NOTCH 信号传导在 POU1F1 细胞命运获得中没有直接作用。相比之下，在 POMC 谱系中，NICD 表达诱导向祖细胞样状态的回归，表明 NOTCH 途径特异性地阻止 POMC 细胞分化。这些结果对垂体发育、可塑性和再生具有重要意义。在胚胎小鼠垂体的不同细胞谱系中激活 NOTCH 信号揭示了一种出乎意料的差异敏感性，这因此揭示了内分泌谱系发育和可塑性的新方面。
