| First Author | Lee JA | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 25 | Pages | 9636-9650 |
| PubMed ID | 29735529 | Mgi Jnum | J:264469 |
| Mgi Id | MGI:6196908 | Doi | 10.1074/jbc.RA118.002012 |
| Citation | Lee JA, et al. (2018) Global loss of leucine carboxyl methyltransferase-1 causes severe defects in fetal liver hematopoiesis. J Biol Chem 293(25):9636-9650 |
| abstractText | Leucine carboxyl methyltransferase-1 (LCMT-1) methylates the C-terminal leucine alpha-carboxyl group of the catalytic subunits of the protein phosphatase 2A (PP2A) subfamily of protein phosphatases, PP2Ac, PP4c, and PP6c. LCMT-1 differentially regulates the formation and function of a subset of the heterotrimeric complexes that PP2A and PP4 form with their regulatory subunits. Global LCMT-1 knockout causes embryonic lethality in mice, but LCMT-1 function in development is unknown. In this study, we analyzed the effects of global LCMT-1 loss on embryonic development. LCMT-1 knockout causes loss of PP2Ac methylation, indicating that LCMT-1 is the sole PP2Ac methyltransferase. PP2A heterotrimers containing the Balpha and Bdelta B-type subunits are dramatically reduced in whole embryos, and the steady-state levels of PP2Ac and the PP2A structural A subunit are also down approximately 30%. Strikingly, global loss of LCMT-1 causes severe defects in fetal hematopoiesis and usually death by embryonic day 16.5. Fetal livers of homozygous lcmt-1 knockout embryos display hypocellularity, elevated apoptosis, and greatly reduced numbers of hematopoietic stem and progenitor cell-enriched Kit(+)Lin(-)Sca1(+) cells. The percent cycling cells and mitotic indices of WT and lcmt-1 knockout fetal liver cells are similar, suggesting that hypocellularity may be due to a combination of apoptosis and/or defects in specification, self-renewal, or survival of stem cells. Indicative of a possible intrinsic defect in stem cells, noncompetitive and competitive transplantation experiments reveal that lcmt-1 loss causes a severe multilineage hematopoietic repopulating defect. Therefore, this study reveals a novel role for LCMT-1 as a key player in fetal liver hematopoiesis. |
