Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade
Homeostatic and tumourigenic activity of SOX2+ pituitary stem cells is controlled by the LATS/YAP/TAZ cascade
复制标题
SOX2 垂体干细胞的稳态和致瘤活性由 LATS/YAP/TAZ 级联控制
DOI：
10.1101/492165
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Lodge E
中科院分区：
文献类型：
--
作者：
Lodge E
SOX2 阳性垂体干细胞 (PSC) 在胚胎时期就被指定并持续存在于整个生命周期，产生所有垂体内分泌谱系。我们之前已经展示了发育中和出生后哺乳动物垂体中 STK/LATS/YAP/TAZ 信号级联的激活。在这里，我们研究了该通路在垂体发育和 SOX2 细胞区室调节过程中的功能。通过功能丧失和功能获得的遗传方法，我们揭示了在发育过程中限制 YAP/TAZ 激活对于 SOX2+ PSC 的正常器官大小和规格至关重要。出生后 LATS 激酶的缺失和随后 YAP/TAZ 的上调会导致 SOX2+ PSC 不受控制的克隆扩张并破坏其分化，从而导致非分泌性、侵袭性垂体肿瘤的形成。相比之下，单独持续表达 YAP 会导致 SOX2+ PSC 的扩增，能够分化且缺乏致瘤潜力。我们的研究结果表明，LATS/YAP/TAZ 信号级联是正常垂体生理学和肿瘤发生中 PSC 调节的重要组成部分。
SOX2 positive pituitary stem cells (PSCs) are specified embryonically and persist throughout life, giving rise to all pituitary endocrine lineages. We have previously shown the activation of the STK/LATS/YAP/TAZ signalling cascade in the developing and postnatal mammalian pituitary. Here, we investigate the function of this pathway during pituitary development and in the regulation of the SOX2 cell compartment. Through loss- and gain-of-function genetic approaches, we reveal that restricting YAP/TAZ activation during development is essential for normal organ size and specification from SOX2+ PSCs. Postnatal deletion of LATS kinases and subsequent upregulation of YAP/TAZ leads to uncontrolled clonal expansion of the SOX2+ PSCs and disruption of their differentiation, causing the formation of non-secreting, aggressive pituitary tumours. In contrast, sustained expression of YAP alone results in expansion of SOX2+ PSCs capable of differentiation and devoid of tumourigenic potential. Our findings identify the LATS/YAP/TAZ signalling cascade as an essential component of PSC regulation in normal pituitary physiology and tumourigenesis.
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影响因子：
50.3
作者：
Zhou D;Conrad C;Xia F;Park JS;Payer B;Yin Y;Lauwers GY;Thasler W;Lee JT;Avruch J;Bardeesy N
通讯作者：
Bardeesy N
影响因子：
10.5
作者：
INGRAHAM, HA;LALA, DS;PARKER, KL
通讯作者：
PARKER, KL
影响因子：
3.2
作者：
Nolan, LA;Kavanagh, E;Levy, A
通讯作者：
Levy, A
影响因子：
4.1
作者：
LEWIS, AJ;COOPER, PW;SCHWARTZ, ML
通讯作者：
SCHWARTZ, ML
正常的垂体发展需要同型转录因子HESX1和SIX3之间的遗传相互作用。
影响因子：
2.7
作者：
Gaston-Massuet, Carles;Andoniadou, Cynthia L.;Signore, Massimo;Sajedi, Ezat;Bird, Sophie;Turner, James M. A.;Martinez-Barbera, Juan Pedro
通讯作者：
Martinez-Barbera, Juan Pedro