Rab5c-mediated endocytic trafficking regulates hematopoietic stem and progenitor cell development via Notch and AKT signaling
Rab5c-mediated endocytic trafficking regulates hematopoietic stem and progenitor cell development via Notch and AKT signaling
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DOI：
10.1371/journal.pbio.3000696
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发表时间：
2020-04-01
期刊：
影响因子：
9.8
通讯作者：
Liu, Feng
中科院分区：
文献类型：
--
作者：
Heng, Jian;Lv, Peng;Liu, Feng
众所周知，各种发育信号在造血干细胞和祖细胞（HSPC）的产生中起着不同的作用；然而，这些信号通路是如何协调的仍然不完全清楚。在这里，我们报道了Rab5c在斑马鱼胚胎中通过Notch和AKT信号的内吞运输来规范HSPC是必不可少的。Rab5c缺乏导致HSPC生产缺陷。在机制上，Rab5c通过Notch配体和受体的内噬运输来调节造血内皮（HE）的规格。我们进一步发现，通过AKT信号传导，核内体中Rab5c和Appl1的相互作用是背主动脉腹壁上HE存活所必需的。有趣的是，Rab5c过激活也可导致HSPC产生缺陷，这归因于过度内溶酶体运输诱导Notch信号缺陷。综上所述，我们的研究结果确立了rab5c介导的内噬运输在HSPC发育中的先前未被认识到的作用，并为如何协调时空信号以准确执行细胞命运转变提供了新的见解。
It is well known that various developmental signals play diverse roles in hematopoietic stem and progenitor cell (HSPC) production; however, how these signaling pathways are orchestrated remains incompletely understood. Here, we report that Rab5c is essential for HSPC specification by endocytic trafficking of Notch and AKT signaling in zebrafish embryos. Rab5c deficiency leads to defects in HSPC production. Mechanistically, Rab5c regulates hemogenic endothelium (HE) specification by endocytic trafficking of Notch ligands and receptor. We further show that the interaction between Rab5c and Appl1 in the endosome is required for the survival of HE in the ventral wall of the dorsal aorta through AKT signaling. Interestingly, Rab5c overactivation can also lead to defects in HSPC production, which is attributed to excessive endolysosomal trafficking inducing Notch signaling defect. Taken together, our findings establish a previously unrecognized role of Rab5c-mediated endocytic trafficking in HSPC development and provide new insights into how spatiotemporal signals are orchestrated to accurately execute cell fate transition.