Lysophosphatidic Acid Signaling in the Nervous System

Yung, Yun C.; Stoddard, Nicole C.; Mirendil, Hope; Chun, Jerold

doi:10.1016/j.neuron.2015.03.043

Cited by 52 publications

(94 citation statements)

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“…More recently, lipids have become recognized as a distinct type of chemical messenger in the nervous system that appear to be generated at the time of their intended action rather than amassed in vesicles (2)(3)(4)(5). This "on-demand" model for production implicates lipid biosynthetic enzymes as major regulators of chemical signaling in the central nervous system (CNS).…”

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confidence: 99%

“…Many bioactive lipids share structural features and can be, in principle, connected to one another through multistep metabolic routes (2,18,19), suggesting the potential for cross-talk among lipid signaling pathways in vivo. Such cross-talk could produce more sophisticated forms of integrated or counter-balanced signal transduction to affect complex physiological or disease processes in a dynamic manner.…”

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confidence: 99%

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Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

Ogasawara

Deng

Viader

et al. 2015

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

129

190

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Diacylglycerol lipases (DAGLα and DAGLβ) convert diacylglycerol to the endocannabinoid 2-arachidonoylglycerol. Our understanding of DAGL function has been hindered by a lack of chemical probes that can perturb these enzymes in vivo. Here, we report a set of centrally active DAGL inhibitors and a structurally related control probe and their use, in combination with chemical proteomics and lipidomics, to determine the impact of acute DAGL blockade on brain lipid networks in mice. Within 2 h, DAGL inhibition produced a striking reorganization of bioactive lipids, including elevations in DAGs and reductions in endocannabinoids and eicosanoids. We also found that DAGLα is a short half-life protein, and the inactivation of DAGLs disrupts cannabinoid receptor-dependent synaptic plasticity and impairs neuroinflammatory responses, including lipopolysaccharide-induced anapyrexia. These findings illuminate the highly interconnected and dynamic nature of lipid signaling pathways in the brain and the central role that DAGL enzymes play in regulating this network.

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confidence: 99%

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confidence: 99%

Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

Ogasawara

Deng

Viader

et al. 2015

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

129

190

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“…LPA signalling influences a number of developmental processes within the nervous system (Yung et al, 2015). LPA is found in varying abundance in the embryonic brain, neural tube, choroid plexus, meninges, blood vessels, spinal cord and cerebrospinal fluid at nanomolar to micromolar concentrations (Yung et al, 2014).…”

Section: Lpa In the Nervous Systemmentioning

confidence: 99%

Lysophosphatidic acid signalling in development

et al. 2015

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Lysophosphatidic acid (LPA) is a bioactive phospholipid that is present in all tissues examined to date. LPA signals extracellularly via cognate G protein-coupled receptors to mediate cellular processes such as survival, proliferation, differentiation, migration, adhesion and morphology. These LPA-influenced processes impact many aspects of organismal development. In particular, LPA signalling has been shown to affect fertility and reproduction, formation of the nervous system, and development of the vasculature. Here and in the accompanying poster, we review the developmentally related features of LPA signalling.

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“…Lysophosphatidic acid (LPA) is a bioactive lipid mediator that directs multiple fundamental biological processes, including those that regulate cell fate, such as survival, proliferation and apoptosis, and those that regulate cell motility, such as extension and contraction of the actin cytoskeleton (1)(2)(3). The effects of LPA on cells depend on their expression of LPA-specific G-protein coupled receptors (e.g., LPA [1][2][3][4][5][6] [1,4]).…”

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confidence: 99%

“…The effects of LPA on cells depend on their expression of LPA-specific G-protein coupled receptors (e.g., LPA [1][2][3][4][5][6] [1,4]). Moreover, different downstream signaling pathways couple to each LPA receptor, enabling the same LPA receptor to mediate opposing effects in different cells types (5).…”

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confidence: 99%

Lysophosphatidic Acid Signaling through the Lysophosphatidic Acid-1 Receptor Is Required for Alveolarization

Funke

Knudsen

Lagares³

et al. 2016

Am J Respir Cell Mol Biol

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Lysophosphatidic acid (LPA) signaling through one of its receptors, LPA 1 , contributes to both the development and the pathological remodeling after injury of many organs. Because we found previously that LPA-LPA 1 signaling contributes to pulmonary fibrosis, here we investigated whether this pathway is also involved in lung development. Quantitative assessment of lung architecture of LPA 1 -deficient knockout (KO) and wild-type (WT) mice at 3, 12, and 24 weeks of age using design-based stereology suggested the presence of an alveolarization defect in LPA 1 KO mice at 3 weeks, which persisted as alveolar numbers increased in WT mice into adulthood. Across the ages examined, the lungs of LPA 1 KO mice exhibited decreased alveolar numbers, septal tissue volumes, and surface areas, and increased volumes of the distal airspaces. Elastic fibers, critical to the development of alveolar septa, appeared less organized and condensed and more discontinuous in KO alveoli starting at P4. Tropoelastin messenger RNA expression was decreased in KO lungs, whereas expression of matrix metalloproteinases degrading elastic fibers was either decreased or unchanged. These results are consistent with the abnormal lung phenotype of LPA 1 KO mice, being attributable to reduced alveolar septal formation during development, rather than to increased septal destruction as occurs in the emphysema of chronic obstructive pulmonary disease. Peripheral septal fibroblasts and myofibroblasts, which direct septation in late alveolarization, demonstrated reduced production of tropoelastin and matrix metalloproteinases, and diminished LPA-induced migration, when isolated from LPA 1 KO mice. Taken together, our data suggest that LPA-LPA 1 signaling is critically required for septation during alveolarization.

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Lysophosphatidic Acid Signaling in the Nervous System

Abstract: In the original Supplemental Information for this Article, the time of treatment with tamoxifen given in Figure S3 was P1, but the actual time of treatment was P21. This has now been corrected in the Supplemental Information online.

Cited by 52 publications

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Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

Lysophosphatidic acid signalling in development

Lysophosphatidic Acid Signaling through the Lysophosphatidic Acid-1 Receptor Is Required for Alveolarization

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