Global loss of leucine carboxyl methyltransferase-1 causes severe defects in fetal liver hematopoiesis
Open accessAbstract
Leucine carboxyl methyltransferase-1 (LCMT-1) methylates the C-terminal leucine α-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 Bα and Bδ 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 ∼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.
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A rather similar phenotype was observed in Lcmt1 knockout mice lacking detectable LCMT-1, which is predicted to majorly affect PP2A holoenzyme formation with B55 subunits.
“Interestingly, a rather similar phenotype was observed in Lcmt1 KO mice, lacking any detectable expression of the PP2A methyltransferase LCMT-1, which is predicted to majorly affect PP2A holoenzyme formation with B55 subunits [26,[39][40][41].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [41]
The large majority of LCMT-1 knockout embryos died between E14.5 and E16.5; 5% died before E12.5.
“The large majority of LCMT-1 KO embryos died between E14.5 and E16.5; 5% died before E12.5 [41].”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [41]
At E12.5 in Lcmt1 knockout, more than 95% decreased PP2A-C methylation was seen, accompanied by 30% reduction in total A and C subunit levels and 92% reduction in PP2A-B55α/δ formation.
“At E12.5, > 95% decreased PP2A-C methylation was seen, accompanied by 30% reduction in total A and C subunit levels and a 92% reduction in PP2A-B55α/δ formation (due to 80% reduction in B55α/δ expression, and 40% reduction in C binding to B55).”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [41]
In mice with a gene-trap insertion in the first intron of Lcmt1 (German Gene Trap consortium clone), embryonic lethality occurs between E14.5 and E16.5, with 5% dying before E12.5.
“-Embryonic lethality between E14.5 and E16.5 (5% die before E12.5) [26,39,41]”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [41]
In Lcmt1 -/- E14.5 MEFs, formation of PP2A-B55 and PP4-PPP4R1 complexes is selectively defective.
“-In -/-E14.5 MEFs: decreased methylation of PP2A, PP4 and PP6; | selective defects in PP2A-B55 and PP4-PPP4R1 complex formation”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [41]
At E12.5, Lcmt1 gt/gt embryos have a fetal liver hematopoiesis defect affecting all lineages.
“-At E12.5: reduced embryo and liver weight; fetal liver hematopoiesis | defect (all lineages affected); misshapen eyes; indentation of the back | of the head”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [41]
At E12.5, Lcmt1 gt/gt embryos have misshapen eyes.
“-At E12.5: reduced embryo and liver weight; fetal liver hematopoiesis | defect (all lineages affected); misshapen eyes; indentation of the back | of the head”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [41]
In Lcmt1 -/- E14.5 MEFs, methylation of PP2A, PP4 and PP6 is decreased.
“-In -/-E14.5 MEFs: decreased methylation of PP2A, PP4 and PP6; | selective defects in PP2A-B55 and PP4-PPP4R1 complex formation”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [41]
At E12.5, Lcmt1 gt/gt embryos have reduced embryo and liver weight.
“-At E12.5: reduced embryo and liver weight; fetal liver hematopoiesis | defect (all lineages affected); misshapen eyes; indentation of the back | of the head”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [41]
At E12.5, Lcmt1 gt/gt embryos have an indentation of the back of the head.
“-At E12.5: reduced embryo and liver weight; fetal liver hematopoiesis | defect (all lineages affected); misshapen eyes; indentation of the back | of the head”
From Physiologic functions of PP2A: Lessons from genetically modified mice (2019) · cites this paper as [41]
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Physiologic functions of PP2A: Lessons from genetically modified mice
Reynhout, S., & Janssens, V. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2018.07.010 · Cited by 124 · see citing works
- Authors
- Lee, J. A., Wang, Z., Sambo, D., Bunting, K. D., & Pallas, D. C.
- Affiliations
- Winship Cancer Institute (US)
- Emory University (US)
- Corresponding author
- Pallas, David C.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2018-06
- Volume
- 293
- Issue
- 25
- Pages
- 9636-9650
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC6016458
- OpenAlex
- W2799780361
- Cited by
- 16
- References
- 58
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 1
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Cancer Institute (NCI) (R01CA57327, P30CA138292, Predoctoral Fellowship F31CA123640)
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01DK059380)
- Emory University Research Committee (URC award)
- Aflac Cancer and Blood Disorder Center (Faculty Award)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- protein phosphatase 2A, fetal liver hematopoiesis, embryonic lethality, hematopoietic stem cells, hematopoietic progenitor cells, apoptosis, hematopoietic repopulation
- MeSH terms
- Animals, Embryo, Mammalian, Fetus, Hematopoiesis, Liver, Protein O-Methyltransferase, Apoptosis, Mice, Knockout, DNA Methylation, Cell Proliferation, Mice, Protein Phosphatase 2
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