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Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2020-03-30 , DOI: 10.1038/s41556-020-0483-2 Aurélia Huyghe 1 , Giacomo Furlan 1 , Duygu Ozmadenci 1 , Christina Galonska 2 , Jocelyn Charlton 2, 3, 4, 5 , Xavier Gaume 1 , Noémie Combémorel 1 , Christina Riemenschneider 2 , Nicolas Allègre 6 , Jenny Zhang 7 , Pauline Wajda 1 , Nicolas Rama 8 , Pauline Vieugué 8 , Isabelle Durand 9 , Marie Brevet 10 , Nicolas Gadot 10 , Thomas Imhof 11 , Bradley J Merrill 7 , Manuel Koch 11 , Patrick Mehlen 8, 12 , Claire Chazaud 6 , Alexander Meissner 2, 3, 4, 5 , Fabrice Lavial 1
Nature Cell Biology ( IF 17.3 ) Pub Date : 2020-03-30 , DOI: 10.1038/s41556-020-0483-2 Aurélia Huyghe 1 , Giacomo Furlan 1 , Duygu Ozmadenci 1 , Christina Galonska 2 , Jocelyn Charlton 2, 3, 4, 5 , Xavier Gaume 1 , Noémie Combémorel 1 , Christina Riemenschneider 2 , Nicolas Allègre 6 , Jenny Zhang 7 , Pauline Wajda 1 , Nicolas Rama 8 , Pauline Vieugué 8 , Isabelle Durand 9 , Marie Brevet 10 , Nicolas Gadot 10 , Thomas Imhof 11 , Bradley J Merrill 7 , Manuel Koch 11 , Patrick Mehlen 8, 12 , Claire Chazaud 6 , Alexander Meissner 2, 3, 4, 5 , Fabrice Lavial 1
Affiliation
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In mouse embryonic stem cells (mESCs), chemical blockade of Gsk3α/β 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 Gsk3α/β 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 Gsk3α/β and stabilize β-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.
中文翻译：
Netrin-1通过Neo1和Unc5b对Wnt和MAPK信号转导的共同调控来促进幼稚的多能性。
在小鼠胚胎干细胞（mESCs）中，对Gsk3α/β和Mek1 / 2（2i）的化学阻断指示了自我更新的基态，其内源性诱导剂未知。在这里，我们显示轴突指导线索Netrin-1通过触发mESCs中的深刻信号传导，转录组和表观遗传学变化来促进幼稚的多能性。此外，我们证明Netrin-1可以替代Gsk3α/β和Mek1 / 2的阻滞剂，以结合白血病抑制因子维持mESC的自我更新，并调节小鼠多能囊胚的形成。从机理上讲，我们揭示了Netrin-1及其受体Neo1和Unc5B的平衡如何在小鼠和人类ESC中共同调节Wnt和MAPK途径。Netrin-1诱导Fak激酶失活Gsk3α/β并稳定β-catenin，同时增加含Ppp2r2c的Pp2a复合物的磷酸酶活性，从而降低Erk1 / 2活性。总的来说，这项工作确定了Netrin-1是多能性的调节剂，并揭示了它在mESC中根据其受体剂量介导不同的作用，为平衡自我更新和血统承诺开辟了前景。
更新日期：2020-04-24
中文翻译：
Netrin-1通过Neo1和Unc5b对Wnt和MAPK信号转导的共同调控来促进幼稚的多能性。
在小鼠胚胎干细胞（mESCs）中，对Gsk3α/β和Mek1 / 2（2i）的化学阻断指示了自我更新的基态，其内源性诱导剂未知。在这里，我们显示轴突指导线索Netrin-1通过触发mESCs中的深刻信号传导，转录组和表观遗传学变化来促进幼稚的多能性。此外，我们证明Netrin-1可以替代Gsk3α/β和Mek1 / 2的阻滞剂，以结合白血病抑制因子维持mESC的自我更新，并调节小鼠多能囊胚的形成。从机理上讲，我们揭示了Netrin-1及其受体Neo1和Unc5B的平衡如何在小鼠和人类ESC中共同调节Wnt和MAPK途径。Netrin-1诱导Fak激酶失活Gsk3α/β并稳定β-catenin，同时增加含Ppp2r2c的Pp2a复合物的磷酸酶活性，从而降低Erk1 / 2活性。总的来说，这项工作确定了Netrin-1是多能性的调节剂，并揭示了它在mESC中根据其受体剂量介导不同的作用，为平衡自我更新和血统承诺开辟了前景。
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