Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling
Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling
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DOI：
10.1038/s41556-020-0483-2
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发表时间：
2020-03-30
影响因子：
21.3
通讯作者：
Lavial, Fabrice
中科院分区：
文献类型：
--
作者：
Huyghe, Aurelia;Furlan, Giacomo;Lavial, Fabrice
Netrin-1通过精确的Neo 1/Unc 5 B化学计量，促进幼稚多能性、胚胎干细胞自我更新与白血病抑制因子的组合，以及小鼠体内外胚层的形成。在小鼠胚胎干细胞（mESC）中，Gsk 3 α/β和Mek 1/2（2 i）的化学阻断指示自我更新基态，其内源性诱导剂未知。在这里，我们表明，轴突导向因子Netrin-1通过触发mESC中深刻的信号传导、转录组和表观遗传变化来促进幼稚多能性。此外，我们证明Netrin-1可以替代Gsk 3 α/β和Mek 1/2的阻断，与白血病抑制因子结合维持mESC的自我更新，并调节小鼠多能囊胚的形成。从机制上讲，我们揭示了Netrin-1及其受体Neo 1和Unc 5 B的平衡如何共同调节小鼠和人类胚胎干细胞中的Wnt和MAPK通路。Netrin-1诱导Fak激酶转化为Erk 3 α/β并稳定β-连环蛋白，同时增加含有Ppp 2 r2 c的Pp 2a复合物的磷酸酶活性以降低Erk 1/2活性。总的来说，这项工作将Netrin-1确定为多能性的调节因子，并揭示它根据其受体剂量介导mESC的不同作用，为平衡自我更新和谱系承诺开辟了前景。
Netrin-1, via precise Neo1/Unc5B stoichiometry, promotes naive pluripotency, embryonic stem cell self-renewal in combination with leukaemia inhibitory factor, and the formation of the mouse epiblast in vivo.In mouse embryonic stem cells (mESCs), chemical blockade of Gsk3 alpha/beta and Mek1/2 (2i) instructs a self-renewing ground state whose endogenous inducers are unknown. Here we show that the axon guidance cue Netrin-1 promotes naive pluripotency by triggering profound signalling, transcriptomic and epigenetic changes in mESCs. Furthermore, we demonstrate that Netrin-1 can substitute for blockade of Gsk3 alpha/beta and Mek1/2 to sustain self-renewal of mESCs in combination with leukaemia inhibitory factor and regulates the formation of the mouse pluripotent blastocyst. Mechanistically, we reveal how Netrin-1 and the balance of its receptors Neo1 and Unc5B co-regulate Wnt and MAPK pathways in both mouse and human ESCs. Netrin-1 induces Fak kinase to inactivate Gsk3 alpha/beta and stabilize beta-catenin while increasing the phosphatase activity of a Ppp2r2c-containing Pp2a complex to reduce Erk1/2 activity. Collectively, this work identifies Netrin-1 as a regulator of pluripotency and reveals that it mediates different effects in mESCs depending on its receptor dosage, opening perspectives for balancing self-renewal and lineage commitment.