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LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells
Nature Communications ( IF 16.6 ) Pub Date : 2021-05-10 , DOI: 10.1038/s41467-021-22813-w
María Ángeles Marqués-Torrejón , Charles A. C. Williams , Benjamin Southgate , Neza Alfazema , Melanie P. Clements , Claudia Garcia-Diaz , Carla Blin , Nerea Arranz-Emparan , Jane Fraser , Noor Gammoh , Simona Parrinello , Steven M. Pollard

Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.



中文翻译:

LRIG1是退出成年神经干细胞静止期的守门人

成人神经干细胞(NSC)必须严格控制静止和增殖。单细胞分析表明,随着NSC退出静止状态,细胞状态将连续不断。在这里,我们捕获并表征了体外启动的静态NSC,并将LRIG1鉴定为重要的调节剂。我们表明,BMP-4信号传导诱导休眠的非循环静止状态(d-qNSCs),而结合的BMP-4 / FGF-2信号传导诱导蓄势的静止状态准备重新进入细胞周期。引发的静态NSC(p-qNSCs)由高水平的LRIG1和CD9以及干扰素反应信号决定,可以有效地植入成人脑室下区域(SVZ)的环境中。Lrig1的遗传破坏SVZ NSC体内的体内增殖会增强。从机制上讲,LRIG1通过使EGFR蛋白水平增加但限制信号传导激活,使静态NSC引发细胞周期重新进入和EGFR反应。因此,LRIG1是NSC退出静止状态的重要功能调节剂。

更新日期:2021-05-10
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