The Roles of Diacylglycerol Kinases in the Central Nervous System: Review of Genetic Studies in Mice

Ishisaka, Mitsue; Hara, Hideaki

doi:10.1254/jphs.13r07cr

Cited by 36 publications

(25 citation statements)

References 82 publications

(79 reference statements)

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“…DGK deficiencies cause an imbalance between DAG and PA and affect cellular signaling (45). DGKs are mostly expressed in the brain, where (for those that have been studied) they influence dendritic spine morphology and synaptic plasticity (46,47). The role of each DGK seems to differ based on its distinct localization or structure, suggesting that each has evolved specialized functions.…”

Section: Discussionmentioning

confidence: 99%

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

Tabet

Moutin

Becker

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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Fragile X syndrome (FXS) is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) in neurons. In the mouse, the lack of FMRP is associated with an excessive translation of hundreds of neuronal proteins, notably including postsynaptic proteins. This local protein synthesis deregulation is proposed to underlie the observed defects of glutamatergic synapse maturation and function and to affect preferentially the hundreds of mRNA species that were reported to bind to FMRP. How FMRP impacts synaptic protein translation and which mRNAs are most important for the pathology remain unclear. Here we show by cross-linking immunoprecipitation in cortical neurons that FMRP is mostly associated with one unique mRNA: diacylglycerol kinase kappa (Dgkκ), a master regulator that controls the switch between diacylglycerol and phosphatidic acid signaling pathways. The absence of FMRP in neurons abolishes group 1 metabotropic glutamate receptor-dependent DGK activity combined with a loss of Dgkκ expression. The reduction of Dgkκ in neurons is sufficient to cause dendritic spine abnormalities, synaptic plasticity alterations, and behavior disorders similar to those observed in the FXS mouse model. Overexpression of Dgkκ in neurons is able to rescue the dendritic spine defects of the Fragile X Mental Retardation 1 gene KO neurons. Together, these data suggest that Dgkκ deregulation contributes to FXS pathology and support a model where FMRP, by controlling the translation of Dgkκ, indirectly controls synaptic proteins translation and membrane properties by impacting lipid signaling in dendritic spine.F ragile X syndrome (FXS), the most common cause of inherited intellectual disability and autism, is due to the transcriptional inactivation of the Fragile X Mental Retardation 1 gene (FMR1) (1, 2). The FMR1 knockout (KO) mouse (Fmr1 −/y ) replicates phenotypes similar to human symptoms-including autistic-like behaviors, cognitive deficits, and hyperactivity-as well as abnormal dendritic spine morphology (3). FMR1 encodes Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein associated to polyribosomes and involved in the translational control of mRNAs important for synaptic plasticity (4). Consistent with a posttranscriptional function, the absence of FMRP in Fmr1 −/y mouse causes abnormal signaling of group 1 metabotropic glutamate receptors (mGluRI), leading to several forms of abnormal synaptic plasticity that rely on protein translation (5, 6). Protein expression analyses confirmed a role of FMRP in neuronal translational control (7), but the extent of this control remains unclear. Although several studies focusing on individual mRNA targets (e.g., Fmr1, Map1b, Psd95, App, etc.) suggest specific control by FMRP (2), studies of global translation, including in vivo labeling in the Fmr1 −/y mouse (8), showed thousands of neuronal proteins deregulated in the absence of FMRP, pointing toward a general translational derepression. Studies seeking to identify the transcripts controlled by FMRP identified can...

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Section: Discussionmentioning

confidence: 99%

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

Tabet

Moutin

Becker

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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“…The researches reported that DGK-α knockdown was toxic to human glioblastoma and other cancers, and DGK-α inhibition can slow tumor growth and regulate the glioblastoma survival [12,13]. Out of these isoforms, diacylglycerol kinasesζ (DGKζ) has been implicated in cancers previously, which showed that DGKζ expression was elevated in human metastatic colon cancer cells and essential for cancer invasion [14]. In addition, Tanaka T et al reported that DGKζ acted as a sentinel to control the function of p53 during normal homeostasis and stress responses [15].…”

Section: Introductionmentioning

confidence: 99%

Loss of Diacylglycerol Kinase-Ζ Inhibits Cell Proliferation and Survival in Human Gliomas

Diao

Zhang

et al. 2015

Mol Neurobiol

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Diacylglycerol kinases ζ (DGKζ) is a critical lipid kinase which is involved in phosphatidic acid (PA) generation via diacylglycerol (DAG) phosphorylation. DGKζ is highly expressed in central nervous system and essential for brain development. Studies have indicated that DGKζ is associated with colon cancer invasion and metastasis. However, the involvement of DGKζ in human glioma development remains elusive. Here, we explored the impact and possible mechanisms of DGKζ knockdown on the proliferation and survival of glioma cells. The relationship between DGKζ expression status and human glioma stages was explored in 111 specimens of human gliomas via immunohistochemistry technology. Then the impact of DGKζ on cell proliferation, cell cycle, survival, and colony formation ability was determined in U-87 MG glioma cell lines via lentiviral-mediated small interfering (shRNA) strategy. The influence of DGKζ knockdown on global gene expression in U-87 MGglioma cell lines was further analyzed by microarray platform to reveal the possible molecular mechanisms underlying DGKζ-mediated glioma development and progression. Immunohistochemistry analysis revealed that DGKζ expression is positively correlated with human gliomagrade. Lentiviral-mediated small interfering (shRNA) strategyefficiently reduced DGKζ expression and DGKζ knockdown impaired cell proliferation, inhibited colony formation ability, and induced cell cycle arrest and cell apoptosis in U-87 MG glioma cells. Finally, microarray analysis revealed that multiple cancer-associated pathways and oncogenes were regulated by DGKζ knockdown, which provides insights into underlying mechansims of DGKζ-associated glioma development and progression. Our results established the positive correlation between DGKζ expression and gliomagrade. Furthermore, DGKζ knockdown in human glioma cell lines U-87 MG impaired cell proliferation, inhibited colony formation ability, and induced cell cycle arrest and apoptosis which microarray analysis showed that DGKζ knockdown interrupted multiple oncogenes and cancer-associated pathways. Taken together, we provided confidential evidence for the causal role of DGKζ in glioma development and progression.

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“…Additionally, diacylglycerol kinase delta (Dgk), which produces PTA by phosphorylating DAG [211], was also down-regulated with SCD1 inhibition.…”

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confidence: 99%

“…The increase in total DAG content seen with SCD1 inhibition may partially stem from a decrease in Dgk expression, since a reduction in the conversion of DAG to PTA would cause an accumulation of DAG [211]. As such, DGK is thought to act as an indirect regulator of cell function by controlling levels of DAG and PTA [211].…”

mentioning

confidence: 99%

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Elucidating the roles of stearoyl-CoA desaturase 1 in adipocyte fatty acid metabolism and cellular function

Ralston

2015

Appl. Physiol. Nutr. Metab.

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Worldwide obesity rates have risen to epidemic proportions, with over 600 million obese individuals across the globe. These individuals are prone to obesity-related health complications including type 2 diabetes, hypertension, cancer and cardiovascular disease. Obesity also coincides with the expansion of adipose tissue (AT), which has an important role storing excess calories in the form of triacylglycerol (TAG) within adipocyte lipid droplets. The predominant fatty acids (FAs) comprising adipocyte TAGs are monounsaturated FAs (MUFAs), which are produced by stearoyl-CoA desaturase 1 (SCD1). Specifically, SCD1 converts saturated FAs palmitate (PA) and stearate (SA) into palmitoleate (PMA) and oleate (OA), respectively.Interestingly, whole-body SCD1-deficiency is associated with reduced lipogenesis and adiposity.This places SCD1 as a potential target for obesity therapies; however, our understanding of the mechanisms linking SCD1 with changes in adipocyte function remains unclear. This thesis provides important new insights into how SCD1 impacts adipocyte FA metabolism and cellular function. Using a specific SCD1 inhibitor, changes in lipid metabolism, global gene expression, inflammation, cellular stress and basal insulin signaling were assessed in 3T3-L1 adipocytes.Results demonstrated that SCD1 inhibition caused a reduction in TAGs and phospholipids, which coincided with the down-regulation of genes associated with the biosynthesis of these lipid fractions. Cellular diacylglyerols were increased with SCD1 inhibition and insulin signaling was partially impaired. In contrast, markers of cellular stress were unaltered. Furthermore, the FA composition of each lipid fraction was dramatically modified, with SCD1-inhibited adipocytes specifically up-regulating the elongation of PA to SA. Stable isotope tracer experiments revealed that this elongation was occurring via elongase 6. Additionally, reduced SCD1 activity in adipocytes exacerbated the effects of exogenous SA on markers or inflammation. Taken together, SCD1 activity has many indirect influences on adipocyte metabolism in addition to its role in FA desaturation. Importantly, SCD1 facilitates the storage of FAs in TAGs and the ability of adipocytes to handle exogenous FAs. SCD1 also prevents saturated FA and DAG accumulation, and preserves insulin signaling in adipocytes. Ultimately this thesis highlights the importance of SCD1 in the maintenance of adipocyte cellular function, and emphasizes the wide-ranging impact of SCD1 on adipocyte FA metabolism.iv

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The Roles of Diacylglycerol Kinases in the Central Nervous System: Review of Genetic Studies in Mice

Cited by 36 publications

References 82 publications

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons

Loss of Diacylglycerol Kinase-Ζ Inhibits Cell Proliferation and Survival in Human Gliomas

Elucidating the roles of stearoyl-CoA desaturase 1 in adipocyte fatty acid metabolism and cellular function

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