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.
Hbxip is essential for embryogenesis and regulates embryonic stem cell differentiation through activating mTORC1
These authors contributed equally.
- Award Group:
- Funder(s): National Key Research and Development Program of China
- Award Id(s): 2021YFA1101002
- Funder(s):
- Award Group:
- Funder(s): National Natural Science Foundation of China
- Award Id(s): 31871485
- Funder(s):
- Award Group:
- Funder(s): Natural Science Foundation of Tianjin City
- Award Id(s): 18JCJQJC48400
- Funder(s):
- Award Group:
- Funder(s): China Postdoctoral Science Foundation
- Award Id(s): 2019M660980
- Funder(s):
Currently Viewing Accepted Manuscript - Newer Version Available
Yan Qin, Peiling Ni, Qingye Zhang, Xiao Wang, Xiaoling Du, Zixi Yin, Lingling Wang, Lihong Ye, Lingyi Chen; Hbxip is essential for embryogenesis and regulates embryonic stem cell differentiation through activating mTORC1. Development 2022; dev.200527. doi: https://doi.org/10.1242/dev.200527
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