Hbxip is essential for embryogenesis and regulates embryonic stem cell differentiation through activating mTORC1.
Hbxip is essential for embryogenesis and regulates embryonic stem cell differentiation through activating mTORC1.
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Hbxip 对于胚胎发生至关重要，并通过激活 mTORC1 调节胚胎干细胞分化。
DOI：
10.1242/dev.200527
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发表时间：
2022
期刊：
影响因子：
4.6
通讯作者：
Lingyi Chen
中科院分区：
文献类型：
--
作者：
Yanrong Qin;Peiling Ni;Qingye Zhang;Xiao Wang;X. Du;Zixi Yin;Lingling Wang;L. Ye;Lingyi Chen
Hbxip，也称为Lamtor 5，已被充分表征为各种癌症中的转录共激活因子。然而，Hbxip在正常发育中的作用仍未被探索。在这里，我们证明了Hbxip的纯合敲除导致胚胎死亡，在E7.5左右生长迟缓，并且Hbxip的耗尽损害胚胎干细胞（ESC）的自我更新，多能性基因的表达降低，细胞增殖降低，集落形成能力降低。此外，Hbxip-/-ESC和E7.5胚胎都显示出外胚层和中胚层分化的缺陷。从机制上讲，Hbxip与Ragulator复合物的其他组分相互作用，这是氨基酸激活mTORC 1所必需的。重要的是，缺乏Ragulator亚基Lamtor 3或Lamtor 4的ESC显示出与Hbxip-/-ESC相似的分化缺陷。此外，Hbxip-/-、p14-/-和p18-/-小鼠缺乏Ragulator复合物的亚基，也具有相似的表型、胚胎致死性和E7-8前后生长迟缓。因此，我们得出结论，Hbxip通过激活mTORC 1信号传导，在外胚层的发育和分化以及ESC的自我更新和分化中起着关键作用。
Hbxip, also named Lamtor5, has been well characterized as a transcriptional coactivator in various cancers. However, the role of Hbxip in normal development remains unexplored. Here, we demonstrated that homozygous knockout of Hbxip leads to embryonic lethality, with retarded growth around E7.5, and that depletion of Hbxip compromises the self-renewal of embryonic stem cells (ESCs), with reduced expression of pluripotency genes, reduced cell proliferation, and decreased colony forming capacity. In addition, both Hbxip-/- ESCs and E7.5 embryos display defects in ectodermal and mesodermal differentiation. Mechanistically, Hbxip interacts with other components of the Ragulator complex, which is required for mTORC1 activation by amino acids. Importantly, ESCs depleted of Ragulator subunits, Lamtor3 or Lamtor4, display differentiation defects similar to those of Hbxip-/- ESCs. Moreover, Hbxip-/-, p14-/-, and p18-/- mice, lacking subunits of the Ragulator complex, also share similar phenotypes, embryonic lethality and retarded growth around E7-8. Thus, we conclude that Hbxip plays a pivotal role in the development and differentiation of the epiblast, as well as the self-renewal and differentiation of ESCs, through activating mTORC1 signaling.