Acetylcholinesterase is regulated by exposure of ultraviolet B in skin keratinocytes: A potential inducer of cholinergic urticaria.

Cholinergic urticaria is a dermatological disease characterized by the presence of large patches of red skin and transient hives triggered by factors, such as exercise, sweating, and psychological tension. This skin problem is hypothesized to be attributed to a reduced expression of acetylcholinesterase (AChE), an enzyme responsible for hydrolyzing acetylcholine (ACh). Consequently, ACh is thought to the leak from sympathetic nerves to skin epidermis. The redundant ACh stimulates the mast cells to release histamine, triggering immune responses in skin. Here, the exposure of ultraviolet B in skin suppressed the expression of AChE in keratinocytes, both in in vivo and in vitro models. The decrease of the enzyme was resulted from a declined transcription of ACHE gene mediated by micro-RNAs, that is, miR-132 and miR-212. The levels of miR-132 and miR-212 were markedly induced by exposure to ultraviolet B, which subsequently suppressed the transcriptional rate of ACHE. In the presence of low level of AChE, the overflow ACh caused the pro-inflammatory responses in skin epidermis, including increased secretion of cytokines and COX-2. These findings suggest that ultraviolet B exposure is one of the factors contributing to cholinergic urticaria in skin.

Xiao Cheng Qi Decoction, an Ancient Chinese Herbal Mixture, Relieves Loperamide-Induced Slow-Transit Constipation in Mice: An Action Mediated by Gut Microbiota.

Xiao Cheng Qi (XCQ) decoction, an ancient Chinese herbal mixture, has been used in treating slow-transit constipation (STC) for years. The underlying action mechanism in relieving the clinical symptoms is unclear. Several lines of evidence point to a strong link between constipation and gut microbiota. Short-chain fatty acids (SCFAs) and microbial metabolites have been shown to affect 5-HT synthesis by activating the GPR43 receptor localized on intestinal enterochromaffin cells, since 5-HT receptors are known to influence colonic peristalsis. The objective of this study was to evaluate the efficacy of XCQ in alleviating clinical symptoms in a mouse model of STC induced by loperamide. The application of loperamide leads to a decrease in intestinal transport and fecal water, which is used to establish the animal model of STC. In addition, the relationship between constipation and gut microbiota was determined. The herbal materials, composed of Rhei Radix et Rhizoma (Rhizomes of Rheum palmatum L., Polygonaceae) 55.2 g, Magnoliae Officinalis Cortex (Barks of Magnolia officinalis Rehd. et Wils, Magnoliaceae) 27.6 g, and Aurantii Fructus Immaturus (Fruitlet of Citrus aurantium L., Rutaceae) 36.0 g, were extracted with water to prepare the XCQ decoction. The constipated mice were induced with loperamide (10 mg/kg/day), and then treated with an oral dose of XCQ herbal extract (2.0, 4.0, and 8.0 g/kg/day) two times a day. Mosapride was administered as a positive drug. In loperamide-induced STC mice, the therapeutic parameters of XCQ-treated mice were determined, i.e., (i) symptoms of constipation, composition of gut microbiota, and amount of short-chain fatty acids in feces; (ii) plasma level of 5-HT; and (iii) expressions of the GPR43 and 5-HT4 receptor in colon. XCQ ameliorated the constipation symptoms of loperamide-induced STC mice. In gut microbiota, the treatment of XCQ in STC mice increased the relative abundances of Lactobacillus, Prevotellaceae_UCG_001, Prevotellaceae_NK3B31_group, Muribaculaceae, and Roseburia in feces and decreased the relative abundances of Desulfovibrio, Tuzzerella, and Lachnospiraceae_ NK4A136_group. The levels of SCFAs in stools from the STC group were significantly lower than those the control group, and were greatly elevated via treatment with XCQ. Compared with the STC group, XCQ increased the plasma level of 5-HT and the colonic expressions of the GPR43 and 5-HT4 receptor, significantly. The underlying mechanism of XCQ in anti-constipation could be related to the modulation of gut microbiota, the increase in SCFAs, the increase in plasma 5-HT, and the colonic expressions of the GPR43 and 5-HT4 receptor. Our results indicate that XCQ is a potent natural product that could be a therapeutic strategy for constipation.

Root colonization by beneficial rhizobacteria.

Rhizosphere microbes play critical roles for plant's growth and health. Among them, the beneficial rhizobacteria have the potential to be developed as the biofertilizer or bioinoculants for sustaining the agricultural development. The efficient rhizosphere colonization of these rhizobacteria is a prerequisite for exerting their plant beneficial functions, but the colonizing process and underlying mechanisms have not been thoroughly reviewed, especially for the nonsymbiotic beneficial rhizobacteria. This review systematically analyzed the root colonizing process of the nonsymbiotic rhizobacteria and compared it with that of the symbiotic and pathogenic bacteria. This review also highlighted the approaches to improve the root colonization efficiency and proposed to study the rhizobacterial colonization from a holistic perspective of the rhizosphere microbiome under more natural conditions.

Multicomponent Synthesis of Imidazole-Linked Fully Conjugated 3D Covalent Organic Framework for Efficient Electrochemical Hydrogen Peroxide Production.

The semiconducting properties and applications of three dimensional (3D) covalent organic frameworks (COFs) are greatly hampered because of their long-ranged non-conjugated skeletons and relatively unstable linkages. Here, a robust imidazole-linked fully conjugated 3D covalent organic framework (BUCT-COF-7) is synthesized through the one-pot multicomponent Debus-Radziszewski reaction of the saddle-shaped aldehyde-substituted cyclooctatetrathiophene, pyrene-4,5,9,10-tetraone, and ammonium acetate. The semiconducting BUCT-COF-7, as a metal-free catalyst, shows excellent two electron oxygen reduction reaction (ORR) activity in alkaline medium with high hydrogen peroxide (H2 O2 ) selectivity of 83.4 %. When the BUCT-COF-7 as cathode catalyst is assembled into the electrolyzer, the devices showed high electrochemical production rate of H2 O2 up to 326.9 mmol g-1 h-1 . The accumulative amount of H2 O2 could totally degrade the dye methylene blue via Fenton reaction for wastewater treatment. This is the first report about intrinsic 3D COFs for efficient electrochemical synthesis of H2 O2 , revealing the promising applications of fully conjugated 3D COFs in the environment-related field.

Biocontrol mechanisms of Bacillus: Improving the efficiency of green agriculture.

Species of the genus Bacillus have been widely used for the biocontrol of plant diseases in the demand for sustainable agricultural development. New mechanisms underlying Bacillus biocontrol activity have been revealed with the development of microbiome and microbe-plant interaction research. In this review, we first briefly introduce the typical Bacillus biocontrol mechanisms, such as the production of antimicrobial compounds, competition for niches/nutrients, and induction of systemic resistance. Then, we discussed in detail the new mechanisms of pathogen quorum sensing interference and reshaping of the soil microbiota. The "cry for help" mechanism was also introduced, in which plants can release specific signals under pathogen attack to recruit biocontrol Bacillus for root colonization against invasion. Finally, two emerging strategies for enhancing the biocontrol efficacy of Bacillus agents, including the construction of synthetic microbial consortia and the application of rhizosphere-derived prebiotics, were proposed.

Stromal STAT5-Mediated Trophic Activity Regulates Hematopoietic Niche Factors.

Signal transducer and activator of transcription 5 (STAT5a and STAT5b) are intrinsically critical for normal hematopoiesis but are also expressed in stromal cells. Here, STAT5ab knockout (KO) was generated with a variety of bone marrow hematopoietic and stromal Cre transgenic mouse strains. Vav1-Cre/+STAT5abfl/fl, the positive control for loss of multipotent hematopoietic function, surprisingly dysregulated niche factor mRNA expression, and deleted STAT5ab in CD45neg cells. Single-cell transcriptome analysis of bone marrow from Vav1-Cre/+ wild-type or Vav1-Cre/+STAT5abfl/fl mice showed hematopoietic stem cell (HSC) myeloid commitment priming. Nes+ cells were detected in both CD45neg and CD45+ clusters and deletion of STAT5ab with Nes-Cre caused hematopoietic repopulating defects. To follow up on these promiscuous Cre promoter deletions in CD45neg and CD45+ bone marrow cell populations, more stroma-specific Cre strains were generated and demonstrated a reduction in multipotent hematopoietic progenitors. Functional support for niche-supporting activity was assessed using STAT5-deficient mesenchymal stem cells (MSCs). With Lepr-Cre/+STAT5abfl/fl, niche factor mRNAs were downregulated with validation of reduced IGF-1 and CXCL12 proteins. Furthermore, advanced computational analyses revealed a key role for STAT5ab/Cish balance with Cish strongly co-expressed in MSCs and HSCs primed for differentiation. Therefore, STAT5ab-associated gene regulation supports the bone marrow microenvironment.

Nematode-induced trap formation regulated by the histone H3K4 methyltransferase AoSET1 in the nematode-trapping fungus Arthrobotrys oligospora.

The methylation of lysine 4 of histone H3 (H3K4), catalyzed by the histone methyltransferase KMT2/SET1, has been functionally identified in many pathogenic fungi but remains unexplored in nematode-trapping fungi (NTFs). Here, we report a regulatory mechanism of an H3K4-specific SET1 orthologue, AoSET1, in the typical nematode-trapping fungus Arthrobotrys oligospora. When the fungus is induced by the nematode, the expression of AoSET1 is up-regulated. Disruption of AoSet1 led to the abolishment of H3K4me. Consequently, the yield of traps and conidia of ΔAoSet1 was significantly lower than that of the WT strain, and the growth rate and pathogenicity were also compromised. Moreover, H3K4 trimethylation was enriched mainly in the promoter of two bZip transcription factor genes (AobZip129 and AobZip350) and ultimately up-regulated the expression level of these two transcription factor genes. In the ΔAoSet1 and AoH3K4A strains, the H3K4me modification level was significantly decreased at the promoter of transcription factor genes AobZip129 and AobZip350. These results suggest that AoSET1-mediated H3KEme serves as an epigenetic marker of the promoter region of the targeted transcription factor genes. Furthermore, we found that AobZip129 negatively regulates the formation of adhesive networks and the pathogenicity of downstream AoPABP1 and AoCPR1. Our findings confirm that the epigenetic regulatory mechanism plays a pivotal role in regulating trap formation and pathogenesis in NTFs, and provide novel insights into the mechanisms of interaction between NTFs and nematodes.

Salt Tolerant Bacillus Strains Improve Plant Growth Traits and Regulation of Phytohormones in Wheat under Salinity Stress.

Soil salinity is a major constraint adversely affecting agricultural crops including wheat worldwide. The use of plant growth promoting rhizobacteria (PGPR) to alleviate salt stress in crops has attracted the focus of many researchers due to its safe and eco-friendly nature. The current study aimed to study the genetic potential of high halophilic Bacillus strains, isolated from the rhizosphere in the extreme environment of the Qinghai-Tibetan plateau region of China, to reduce salt stress in wheat plants. The genetic analysis of high halophilic strains, NMCN1, LLCG23, and moderate halophilic stain, FZB42, revealed their key genetic features that play an important role in salt stress, osmotic regulation, signal transduction and membrane transport. Consequently, the expression of predicted salt stress-related genes were upregulated in the halophilic strains upon NaCl treatments 10, 16 and 18%, as compared with control. The halophilic strains also induced a stress response in wheat plants through the regulation of lipid peroxidation, abscisic acid and proline in a very efficient manner. Furthermore, NMCN1 and LLCG23 significantly enhanced wheat growth parameters in terms of physiological traits, i.e., fresh weight 31.2% and 29.7%, dry weight 28.6% and 27.3%, shoot length 34.2% and 31.3% and root length 32.4% and 30.2%, respectively, as compared to control plants under high NaCl concentration (200 mmol). The Bacillus strains NMCN1 and LLCG23 efficiently modulated phytohormones, leading to the substantial enhancement of plant tolerance towards salt stress. Therefore, we concluded that NMCN1 and LLCG23 contain a plethora of genetic features enabling them to combat with salt stress, which could be widely used in different bio-formulations to obtain high crop production in saline conditions.

The Role of Pyoluteorin from Pseudomonas protegens Pf-5 in Suppressing the Growth and Pathogenicity of Pantoea ananatis on Maize.

The rhizospheric bacterium Pseudomonas protegens Pf-5 can colonize the seed and root surfaces of plants, and can protect them from pathogen infection. Secondary metabolites, including lipopeptides and polyketides produced by Pf-5, are involved in its biocontrol activity. We isolated a crude extract from Pf-5. It exhibited significant surface activity and strong antibacterial activity against Pantoea ananatis DZ-12, which causes maize brown rot on leaves. HPLC analysis combined with activity tests showed that the polyketide pyoluteorin in the crude extract participated in the suppression of DZ-12 growth, and that the lipopeptide orfamide A was the major biosurfactant in the crude extract. Further studies indicated that the pyoluteorin in the crude extract significantly suppressed the biofilm formation of DZ-12, and it induced the accumulation of reactive oxygen species in DZ-12 cells. Scanning electron microscopy and transmission electron microscopy observation revealed that the crude extract severely damaged the pathogen cells and caused cytoplasmic extravasations and hollowing of the cells. The pathogenicity of DZ-12 on maize leaves was significantly reduced by the crude extract from Pf-5 in a dose-dependent manner. The polyketide pyoluteorin had strong antibacterial activity against DZ-12, and it has the potential for development as an antimicrobial agent.

Dataset of propylene carbonate based liquid electrolyte mixtures for sodium-ion cells.

In this manuscript, we present rheology, ionic conductivity, density, chromatography, and life cycle analysis data on the PC+X electrolyte system with and without LiClO4. In particular, the data are presented in contact with Na surfaces. In this case, photographic images of electrolyte-sodium mixtures are also shown. The data was analyzed using OriginPro software to visualize it in an appropriate manner. In our view, the data serve as comparative values, form a basis of a chromatography analysis and are also valuable for modeling. The analysis of the data is presented in the manuscript "Comprehensive characterization of propylene carbonate based liquid electrolyte mixtures for sodium-ion cells" [1].

Linear-based gain-determining method for adaptive backstepping controller.

This paper presents a linear-based gain-determining method for nonlinear adaptive backstepping controllers. Usually, the gains for nonlinear controllers are tuned by the trial and error method. This method becomes more difficult as the number of gains increases. A user-friendly method is proposed in this work to deal with the problem. Firstly, a linear auxiliary system is formed by separating the linear parts from the nonlinear system. Then, linear state-space techniques are used to determine the gains for state-feedback by the linear auxiliary system. After that, by converting the state-feedback gains to backstepping gains, the gains of the nonlinear backstepping controller can be determined. The proficiency of the gain-determining method is proved by simulations with two linear techniques.

Genomic Features and Molecular Function of a Novel Stress-Tolerant Bacillus halotolerans Strain Isolated from an Extreme Environment.

Due to its topographical position and climatic conditions, the Qinghai-Tibet Plateau possesses abundant microorganism resources. The extremophilic strain KKD1 isolated from Hoh Xil possesses strong stress tolerance, enabling it to propagate under high salinity (13%) and alkalinity (pH 10.0) conditions. In addition, KKD1 exhibits promising biocontrol activity against plant pathogens. To further explore these traits at the genomic level, we performed whole-genome sequencing and analysis. The taxonomic identification according to the average nucleotide identity based on BLAST revealed that KKD1 belongs to Bacillus halotolerans. Genetic screening of KKD1 revealed that its stress resistance mechanism depends on osmotic equilibrium, membrane transportation, and the regulation of ion balance under salt and alkaline stress. The expression of genes involved in these pathways was analyzed using real-time quantitative PCR. The presence of different gene clusters encoding antimicrobial secondary metabolites indicated the various pathways by which KKD1 suppresses phytopathogenic growth. Moreover, the lipopeptides surfactin and fengycin were identified as being significant antifungal components of KKD1. Through comparative genomics analysis, we noticed that KKD1 harbored specific genes involved in stress resistance and biocontrol, thus providing a new perspective on the genomic features of the extremophilic Bacillus species.

Pimozide and Imipramine Blue Exploit Mitochondrial Vulnerabilities and Reactive Oxygen Species to Cooperatively Target High Risk Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease with a high relapse rate. Cytokine receptor targeted therapies are therapeutically attractive but are subject to resistance-conferring mutations. Likewise, targeting downstream signaling pathways has been difficult. Recent success in the development of synergistic combinations has provided new hope for refractory AML patients. While generally not efficacious as monotherapy, BH3 mimetics are very effective in combination with chemotherapy agents. With this in mind, we further explored novel BH3 mimetic drug combinations and showed that pimozide cooperates with mTOR inhibitors and BH3 mimetics in AML cells. The three-drug combination was able to reach cells that were not as responsive to single or double drug combinations. In Flt3-internal tandem duplication (ITD)-positive cells, we previously showed pimozide to be highly effective when combined with imipramine blue (IB). Here, we show that Flt3-ITD+ cells are sensitive to an IB-induced dynamin 1-like (Drp1)-p38-ROS pathway. Pimozide contributes important calcium channel blocker activity converging with IB on mitochondrial oxidative metabolism. Overall, these data support the concept that antioxidants are a double-edged sword. Rationally designed combination therapies have significant promise for further pre-clinical development and may ultimately lead to improved responses.

Tbx15 is required for adipocyte browning induced by adrenergic signaling pathway.

OBJECTIVE: The T-box gene Tbx15 is abundantly expressed in adipose tissues, especially subcutaneous and brown fat. Although its expression is correlated with obesity, its precise biological role in adipose tissue is poorly understood in vivo. Here we investigated the function of Tbx15 in brown adipose thermogenesis and white adipose browning in vivo. METHODS: In the present study, we generated adipose-specific Tbx15 knockout (AKO) mice by crossing Tbx15 floxed mice with adiponectin-Cre mice to delineate Tbx15 function in adipose tissues. We systematically investigated the influence of Tbx15 on brown adipose thermogenesis and white adipose browning in mice, as well as the possible underlying molecular mechanism. RESULTS: Upon cold exposure, adipocyte browning in inguinal adipose tissue was significantly impaired in Tbx15 AKO mice. Furthermore, ablation of Tbx15 blocked adipocyte browning induced by ß3 adrenergic agonist CL 316243, which did not appear to alter the expression of Tbx15. Analysis of DNA binding sites using chromatin-immunoprecipitation (ChIP) revealed that TBX15 bound directly to a key region in the Prdm16 promoter, indicating it regulates transcription of Prdm16, the master gene for adipocyte thermogenesis and browning. Compared to control mice, Tbx15 AKO mice displayed increased body weight gain and decreased whole body energy expenditure in response to high fat diets. CONCLUSION: Taken together, these findings suggest that Tbx15 regulates adipocyte browning and might be a potential target for the treatment of obesity.

Gab2 and Gab3 Redundantly Suppress Colitis by Modulating Macrophage and CD8+ T-Cell Activation.

Inflammatory Bowel Disease (IBD) is a multi-factorial chronic inflammation of the gastrointestinal tract prognostically linked to CD8+ T-cells, but little is known about their mechanism of activation during initiation of colitis. Here, Grb2-associated binding 2/3 adaptor protein double knockout mice (Gab2/3-/-) were generated. Gab2/3-/- mice, but not single knockout mice, developed spontaneous colitis. To analyze the cellular mechanism, reciprocal bone marrow (BM) transplantation demonstrated a Gab2/3-/- hematopoietic disease-initiating process. Adoptive transfer showed individual roles for macrophages and T-cells in promoting colitis development in vivo. In spontaneous disease, intestinal intraepithelial CD8+ but much fewer CD4+, T-cells from Gab2/3-/- mice with rectal prolapse were more proliferative. To analyze the molecular mechanism, reduced PI3-kinase/Akt/mTORC1 was observed in macrophages and T-cells, with interleukin (IL)-2 stimulated T-cells showing increased pSTAT5. These results illustrate the importance of Gab2/3 collectively in signaling responses required to control macrophage and CD8+ T-cell activation and suppress chronic colitis.

Experimental dataset on electrolyte mixtures containing fluoroethylene carbonate and lithium bis(trifluoromethanesulfonyl)imide.

These data and analyses support the research article "Low-flammable electrolytes with fluoroethylene carbonate based solvent mixtures and lithium bis(trifluoromethanesulfonyl)-imide (LiTFSI) for lithium-ion batteries" [1]. The data and analyses presented here include fitted data for density measurements, temperature dependence of density and specific volume of the mixtures, detailed viscosity measurements and conductivity data, current density plots with respect to anodic aluminum dissolution, half-cell C-rate capability of mixtures with the additives used in research article as well as the SEM images and EDX data of the full-cell with the electrolyte selected and controlled.

Linifanib exerts dual anti-obesity effect by regulating adipocyte browning and formation.

Obesity is caused by energy imbalance and accompanied by adipocyte hypertrophy and hyperplasia. Therefore, both enhancement of adipocyte energy expenditure and inhibition of adipogenesis are viable ways to combat obesity. Using the Ucp1-2A-luciferase reporter animal model previously reported by us as a screening platform, a chemical compound Linifanib was identified as a potent inducer of UCP1 expression in primary inguinal adipocytes in vitro and in vivo. Signal pathway analyses showed that Linifanib promoted adipocyte browning by attenuating STAT3 phosphorylation. The effects of Linifanib on adipocyte browning were blocked by the compound, SD19, which activates the STAT3 signaling cascade. Linifanib also inhibited adipocyte differentiation, by blocking mitotic clonal expansion, which could be rescued by STAT3 activator. Taken together, our results indicate that Linifanib might serve as a potential drug for the treatment of obesity.

Production, structure and morphology of exopolysaccharides yielded by submerged fermentation of Antrodia cinnamomea.

Carbon and nitrogen sources in culture medium of Antrodia cinnamomea were optimized to eliminate the interference of exterior macromolecules on exopolysaccharide (EPS) yield by submerged fermentation. The results suggested that culture medium containing 50 g/L of glucose and 20 g/L of yeast extract as the optimal carbon and nitrogen sources could produce 1.03 g/L of exopolysaccharides. After purification, two heteropolysaccharides (AC-EPS1 and AC-EPS2) were obtained and characterized to provide the basic structure information. As the main component of the produced EPS, AC-EPS2 (accounting for 89.63%) was mainly composed of galactose (87.42%) with Mw (molecular weight) and R.M.S. (root-mean-square) radius of 1.18 × 105 g/mol and 25.3 nm, respectively. Furthermore, the spherical and flexible chain morphologies of EPS were observed in different solvents by TEM. The structural and morphological information of purified EPS were significant for further study on their structure-activity relationship and related applications.

The Cooperative Relationship between STAT5 and Reactive Oxygen Species in Leukemia: Mechanism and Therapeutic Potential.

Reactive oxygen species (ROS) are now recognized as important second messengers with roles in many aspects of signaling during leukemogenesis. They serve as critical cell signaling molecules that regulate the activity of various enzymes including tyrosine phosphatases. ROS can induce inactivation of tyrosine phosphatases, which counteract the effects of tyrosine kinases. ROS increase phosphorylation of many proteins including signal transducer and activator of transcription-5 (STAT5) via Janus kinases (JAKs). STAT5 is aberrantly activated through phosphorylation in many types of cancer and this constitutive activation is associated with cell survival, proliferation, and self-renewal. Such leukemic activation of STAT5 is rarely caused by mutation of the STAT5 gene itself but instead by overactive mutant receptors with tyrosine kinase activity as well as JAK, SRC family protein tyrosine kinases (SFKs), and Abelson murine leukemia viral oncogene homolog (ABL) kinases. Interestingly, STAT5 suppresses transcription of several genes encoding antioxidant enzymes while simultaneously enhancing transcription of NADPH oxidase. By doing so, STAT5 activation promotes an overall elevation of ROS level, which acts as a feed-forward loop, especially in high risk Fms-related tyrosine kinase 3 (FLT3) mutant leukemia. Therefore, efforts have been made recently to target ROS in cancer cells. Drugs that are able to either quench ROS production or inversely augment ROS-related signaling pathways both have potential as cancer therapies and may afford some selectivity by activating feedback inhibition of the ROS-STAT5 kinome. This review summarizes the cooperative relationship between ROS and STAT5 and explores the pros and cons of emerging ROS-targeting therapies that are selective for leukemia characterized by persistent STAT5 phosphorylation.

Global loss of leucine carboxyl methyltransferase-1 causes severe defects in fetal liver hematopoiesis.

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.