State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
PLoS Biol. 2020 Apr 10;18(4):e3000696. doi: 10.1371/journal.pbio.3000696. eCollection 2020 Apr.
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.
众所周知，各种发育信号在造血干/祖细胞（HSPC）产生中发挥着不同的作用；然而，这些信号通路是如何协调的仍不完全清楚。在这里，我们报告 Rab5c 通过内吞作用在斑马鱼胚胎中对 Notch 和 AKT 信号转导的调控对 HSPC 特化是必不可少的。Rab5c 缺陷导致 HSPC 产生缺陷。在机制上，Rab5c 通过 Notch 配体和受体的内吞作用调节造血内皮（HE）的特化。我们进一步表明，内体中 Rab5c 和 Appl1 之间的相互作用通过 AKT 信号转导对于主动脉背部腹侧壁中 HE 的存活是必需的。有趣的是，Rab5c 的过度激活也会导致 HSPC 产生缺陷，这归因于过多的内溶酶体运输诱导 Notch 信号缺陷。总之，我们的研究结果确立了 Rab5c 介导的内吞作用在 HSPC 发育中的先前未被认识的作用，并为时空信号如何协调以准确执行细胞命运转变提供了新的见解。
