FBXL12 regulates T‐cell differentiation in a cell‐autonomous manner

Abstract

Aldehyde dehydrogenase (ALDH) activity is a hallmark of stem cells including embryonic, adult tissue and cancer stem cells. The SCF FBXL12 complex is an authentic ubiquitin ligase that targets ALDH3 for degradation. FBXL12 is essential for the differentiation of trophoblast stem cells into specific cell types in the placenta during mouse embryogenesis, but its physiological functions in adult tissues have remained unknown. We have now investigated the role of the FBXL12-ALDH3 axis in the thymus, in which FBXL12 was most abundant among adult mouse tissues examined. During T-cell differentiation, FBXL12 is most abundant in CD4 + CD8 + (DP) cells, with its expression declining as these cells differentiate into CD4 + CD8À or CD4 À CD8 + (SP) cells. T cells of FBXL12-null mice manifested a differentiation block at the DP-SP transition that was associated with ALDH3 accumulation in DP cells. This differentiation block was also apparent in wild-type mouse recipients of FBXL12-null bone marrow transplants as well as in FBXL12-null fetal thymic organ culture, suggesting that it is a cell-autonomous phenomenon in the thymus rather than an indirect effect of altered systemic conditions. Our results thus indicate that, in addition to its role in placental development, the FBXL12-ALDH3 axis is required for maturation of undifferentiated thymocytes.

The autism-related protein CHD8 contributes to the stemness and differentiation of mouse hematopoietic stem cells

“…A BM reconstitution assay was performed as previously described (Nita et al, 2016). Unless indicated otherwise, unfractionated BM cells (4 3 10 5 ) isolated from control, Trp53 -/-/Chd8 F/F , Mx1-Cre/Chd8 F/F , or Trp53 -/-/Mx1-Cre/Chd8 F/F mice (CD45.2) at 4 weeks after poly(I:C) injection were transplanted into lethally irradiated C57BL/6 congenic (CD45.1) recipients together with competitor BM cells (4 3 10 5 ) from C57BL/6 heterozygous congenic (CD45.1/CD45.2) mice.…”

Potential and functional prediction of six circular RNAs as diagnostic markers for colorectal cancer

“…For the cirReNET we built, there were many targeted genes involved in the mechanism of tumor genesis, such as AKT1 ( Liu et al, 2020 ), ErbB2 ( Li et al, 2018a ), ITGB7 ( Sun et al, 2020 ), BAX, MAPK, FBXL12 ( Nita et al, 2016 ), CCL7 ( Zhang et al, 2020b ) and so on. These genes also play very important roles in cell proliferation, apoptosis, movement, T-cell differentiation, adhesion, and polarity formation.…”

Peer Review #1 of "Potential and functional prediction of six circular RNAs as diagnostic markers for colorectal cancer (v0.2)"

“…For the cirReNET we built, there were many targeted genes involved in the mechanism of tumor genesis, such as AKT1 (Liu et al 2020),ErbB2 (Li et al 2018a),ITGB7 (Sun et al 2020),BAX,MAPK,FBXL12 (Nita et al 2016),CCL7 (Zhang et al 2020b) and so on. These genes also play very important roles in cell proliferation, apoptosis, movement, T-cell differentiation, adhesion, and polarity formation.…”