Author Report for: Williams GNo contact information in database for Williams G
Tortoriello G, Beiersdorf J, Romani S, Williams G, Cameron GA, Mackie K, Williams MJ, Di Marzo V, Keimpema E and Harkany T <1 more author(s)> Tortoriello G, Beiersdorf J, Romani S, Williams G, Cameron GA, Mackie K, Williams MJ, Di Marzo V, Keimpema E, Doherty P, Harkany T (- 1) Ref: Cannabis Cannabinoid Res, 6:119, 2021 : PubMed ESTHER: Tortoriello_2021_Cannabis.Cannabinoid.Res_6_119 PubMedSearch: Tortoriello 2021 Cannabis.Cannabinoid.Res 6 119 PubMedID: 33912677 Abstract Introduction: In mammals, sn-1-diacylglycerol lipases (DAGL) generate 2-arachidonoylglycerol (2-AG) that, as the major endocannabinoid, modulates synaptic neurotransmission by acting on CB1 cannabinoid receptors (CB(1)R). Even though the insect genome codes for inaE, which is a DAGL ortholog (dDAGL), its products and their functions remain unknown particularly because insects lack chordate-type cannabinoid receptors. Materials and Methods: Gain-of-function and loss-of-function genetic manipulations were carried out in Drosophila melanogaster, including the generation of both dDAGL-deficient and mammalian CB(1)R-overexpressing flies. Neuroanatomy, dietary manipulations coupled with targeted mass spectrometry determination of arachidonic acid and 2-linoleoyl glycerol (2-LG) production, behavioral assays, and signal transduction profiling for Akt and Erk kinases were employed. Findings from Drosophilae were validated by a CB(1)R-binding assay for 2-LG in mammalian cortical homogenates with functionality confirmed in neurons using high-throughput real-time imaging in vitro. Results: In this study, we show that dDAGL is primarily expressed in the brain and nerve cord of Drosophila during larval development and in adult with 2-LG being its chief product as defined by dietary precursor availability. Overexpression of the human CB(1)R in the ventral nerve cord compromised the mobility of adult Drosophilae. The causality of 2-LG signaling to CB(1)R-induced behavioral impairments was shown by inaE inactivation normalizing defunct motor coordination. The 2-LG-induced activation of transgenic CB(1)Rs affected both Akt and Erk kinase cascades by paradoxical signaling. Data from Drosophila models were substantiated by showing 2-LG-mediated displacement of [(3)H]CP 55,940 in mouse cortical homogenates and reduced neurite extension and growth cone collapsing responses in cultured mouse neurons. Conclusions: Overall, these results suggest that 2-LG is an endocannabinoid-like signal lipid produced by dDAGL in Drosophila. Title: Dementia in Down's syndrome Ballard C, Mobley W, Hardy J, Williams G, Corbett A Ref: Lancet Neurol, 15:622, 2016 : PubMed ESTHER: Ballard_2016_Lancet.Neurol_15_622 PubMedSearch: Ballard 2016 Lancet.Neurol 15 622 PubMedID: 27302127 Abstract Down's syndrome is the most common genetic cause of learning difficulties, and individuals with this condition represent the largest group of people with dementia under the age of 50 years. Genetic drivers result in a high frequency of Alzheimer's pathology in these individuals, evident from neuroimaging, biomarker, and neuropathological findings, and a high incidence of cognitive decline and dementia. However, cognitive assessment is challenging, and diagnostic methods have not been fully validated for use in these patients; hence, early diagnosis remains difficult. Evidence regarding the benefits of cholinesterase inhibitors and other therapeutic options to treat or delay progressive cognitive decline or dementia is very scarce. Despite close similarities with late-onset Alzheimer's disease, individuals with Down's syndrome respond differently to treatment, and a targeted approach to drug development is thus necessary. Genetic and preclinical studies offer opportunities for treatment development, and potential therapies have been identified using these approaches. Title: Assay and Inhibition of the Purified Catalytic Domain of Diacylglycerol Lipase Beta Singh PK, Markwick R, Lu L, Howell FV, Williams G, Doherty P Ref: Biochemistry, 55:2713, 2016 : PubMed ESTHER: Singh_2016_Biochemistry_55_2713 PubMedSearch: Singh 2016 Biochemistry 55 2713 PubMedID: 27115711 Gene_locus related to this paper: human-DAGLB Inhibitor(s) related to this paper: L-Isoleucine-Orlistat Abstract The diacylglycerol lipases (DAGLalpha and DAGLbeta) hydrolyze DAG to generate 2-arachidonoylglycerol (2-AG), the principal endocannabinoid and main precursor of arachidonic acid (AA). The DAGLs make distinct tissue specific contributions toward 2-AG and AA levels, and therefore, selective modulators for these enzymes could play crucial roles toward harnessing their therapeutic potential. Relatively high-throughput assays have recently been reported for DAGLalpha and have proven useful toward the characterization of inhibitors of this enzyme. Similar assays are also warranted for DAGLbeta which was the aim of this study. We first adapted previously reported DAGLalpha membrane assays (using PNPB and DiFMUO as substrates) to measure recombinant DAGLbeta activity in membranes. In contrast to results with DAGLalpha, both substrates provided a relatively limited signal window for measuring DAGLbeta activity, however, an improved window was obtained when employing a third commercially available substrate, EnzChek. In order to further improve on the assay parameters, we successfully purified the glutathione S-transferase (GST) tagged catalytic domain of DAGLbeta. Activity of the enzyme was confirmed using EnzChek as well as two DAGL inhibitors (THL and OMDM-188). The purified DAGLbeta catalytic domain assay described here provides the basis for a relatively clean and convenient assay with the potential to be adapted for high-throughput drug discovery efforts. Title: A novel live cell assay to measure diacylglycerol lipase alpha activity Singh PK, Markwick R, Howell FV, Williams G, Doherty P Ref: Bioscience Reports, 36:, 2016 : PubMed ESTHER: Singh_2016_Biosci.Rep_36_ PubMedSearch: Singh 2016 Biosci.Rep 36 PubMedID: 27013337 Gene_locus related to this paper: human-DAGLA Abstract Diacylglycerol lipase alpha (DAGLalpha) hydrolyses DAG to generate the principal endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) in the central nervous system. DAGLalpha dependent cannabinoid (CB) signalling has been implicated in numerous processes including axonal growth and guidance, adult neurogenesis and retrograde signalling at the synapse. Recent studies have implicated DAGLalpha as an emerging drug target for several conditions including pain and obesity. Activity assays are critical to the drug discovery process; however, measurement of diacylglycerol lipase (DAGL) activity using its native substrate generally involves low-throughput MS techniques. Some relatively high-throughput membrane based assays utilizing surrogate substrates have been reported, but these do not take into account the rate-limiting effects often associated with the ability of a drug to cross the cell membrane. In the present study, we report the development of a live cell assay to measure DAGLalpha activity. Two previously reported DAGLalpha surrogate substrates, p-nitrophenyl butyrate (PNPB) and 6,8-difluoro-4-methylumbelliferyl octanoate (DiFMUO), were evaluated for their ability to detect DAGLalpha activity in live cell assays using a human cell line stably expressing the human DAGLalpha transgene. Following optimization, the small molecule chromogenic substrate PNPB proved to be superior by providing lower background activity along with a larger signal window between transfected and parental cells when compared with the fluorogenic substrate DiFMUO. The assay was further validated using established DAGL inhibitors. In summary, the live cell DAGLalpha assay reported here offers an economical and convenient format to screen for novel inhibitors as part of drug discovery programmes and compliments previously reported high-throughput membrane based DAGL assays. Title: Exploitation of a Novel Binding Pocket in Human Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Discovered through X-ray Fragment Screening Woolford AJ, Pero JE, Aravapalli S, Berdini V, Coyle JE, Day PJ, Dodson AM, Grondin P, Holding FP and Xie R <19 more author(s)> Woolford AJ, Pero JE, Aravapalli S, Berdini V, Coyle JE, Day PJ, Dodson AM, Grondin P, Holding FP, Lee LY, Li P, Manas ES, Marino J, Jr., Martin AC, McCleland BW, McMenamin RL, Murray CW, Neipp CE, Page LW, Patel VK, Potvain F, Rich S, Rivero RA, Smith K, Somers DO, Trottet L, Velagaleti R, Williams G, Xie R (- 19) Ref: Journal of Medicinal Chemistry, 59:5356, 2016 : PubMed ESTHER: Woolford_2016_J.Med.Chem_59_5356 PubMedSearch: Woolford 2016 J.Med.Chem 59 5356 PubMedID: 27167608 Gene_locus related to this paper: human-PLA2G7 Abstract Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 A from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues. Title: Leukocyte esterase in the diagnosis of shoulder periprosthetic joint infection Nelson GN, Paxton ES, Narzikul A, Williams G, Lazarus MD, Abboud JA Ref: J Shoulder Elbow Surg, 24:1421, 2015 : PubMed ESTHER: Nelson_2015_J.Shoulder.Elbow.Surg_24_1421 PubMedSearch: Nelson 2015 J.Shoulder.Elbow.Surg 24 1421 PubMedID: 26279499 Abstract BACKGROUND: Shoulder periprosthetic joint infection (PJI) is difficult to diagnose with traditional methods. Leukocyte esterase (LE) has recently proven to be reliable in knee arthroplasty; however, its value in the shoulder has not been explored. We hypothesized that LE would display high sensitivity and specificity in shoulder PJI. Title: The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling Reisenberg M, Singh PK, Williams G, Doherty P Ref: Philos Trans R Soc Lond B Biol Sci, 367:3264, 2012 : PubMed ESTHER: Reisenberg_2012_Philos.Trans.R.Soc.Lond.B.Biol.Sci_367_3264 PubMedSearch: Reisenberg 2012 Philos.Trans.R.Soc.Lond.B.Biol.Sci 367 3264 PubMedID: 23108545 Abstract The diacylglycerol lipases DAGLs hydrolyse diacylglycerol to generate 2-arachidonoylglycerol 2-AG the most abundant ligand for the CB(1 and CB(2 cannabinoid receptors in the body DAGL-dependent endocannabinoid signalling regulates axonal growth and guidance during development and is required for the generation and migration of new neurons in the adult brain At developed synapses 2-AG released from postsynaptic terminals acts back on presynaptic CB(1 receptors to inhibit the secretion of both excitatory and inhibitory neurotransmitters with this DAGL-dependent synaptic plasticity operating throughout the nervous system Importantly the DAGLs have functions that do not involve cannabinoid receptors For example 2-AG is the precursor of arachidonic acid in a pathway that maintains the level of this essential lipid in the brain and other organs This pathway also drives the cyclooxygenase-dependent generation of inflammatory prostaglandins in the brain which has recently been implicated in the degeneration of dopaminergic neurons in Parkinson's disease Remarkably we still know very little about the mechanisms that regulate DAGL activity-however key insights can be gleaned by homology modelling against other alpha/beta hydrolases and from a detailed examination of published proteomic studies and other databases These identify a regulatory loop with a highly conserved signature motif as well as phosphorylation and palmitoylation as post-translational mechanisms likely to regulate function. Title: Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice Gao Y, Vasilyev DV, Goncalves MB, Howell FV, Hobbs C, Reisenberg M, Shen R, Zhang MY, Strassle BW and Doherty P <12 more author(s)> Gao Y, Vasilyev DV, Goncalves MB, Howell FV, Hobbs C, Reisenberg M, Shen R, Zhang MY, Strassle BW, Lu P, Mark L, Piesla MJ, Deng K, Kouranova EV, Ring RH, Whiteside GT, Bates B, Walsh FS, Williams G, Pangalos MN, Samad TA, Doherty P (- 12) Ref: Journal of Neuroscience, 30:2017, 2010 : PubMed ESTHER: Gao_2010_J.Neurosci_30_2017 PubMedSearch: Gao 2010 J.Neurosci 30 2017 PubMedID: 20147530 Abstract Endocannabinoids (eCBs) function as retrograde signaling molecules at synapses throughout the brain, regulate axonal growth and guidance during development, and drive adult neurogenesis. There remains a lack of genetic evidence as to the identity of the enzyme(s) responsible for the synthesis of eCBs in the brain. Diacylglycerol lipase-alpha (DAGLalpha) and -beta (DAGLbeta) synthesize 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain. However, their respective contribution to this and to eCB signaling has not been tested. In the present study, we show approximately 80% reductions in 2-AG levels in the brain and spinal cord in DAGLalpha(-/-) mice and a 50% reduction in the brain in DAGLbeta(-/-) mice. In contrast, DAGLbeta plays a more important role than DAGLalpha in regulating 2-AG levels in the liver, with a 90% reduction seen in DAGLbeta(-/-) mice. Levels of arachidonic acid decrease in parallel with 2-AG, suggesting that DAGL activity controls the steady-state levels of both lipids. In the hippocampus, the postsynaptic release of an eCB results in the transient suppression of GABA-mediated transmission at inhibitory synapses; we now show that this form of synaptic plasticity is completely lost in DAGLalpha(-/-) animals and relatively unaffected in DAGLbeta(-/-) animals. Finally, we show that the control of adult neurogenesis in the hippocampus and subventricular zone is compromised in the DAGLalpha(-/-) and/or DAGLbeta(-/-) mice. These findings provide the first evidence that DAGLalpha is the major biosynthetic enzyme for 2-AG in the nervous system and reveal an essential role for this enzyme in regulating retrograde synaptic plasticity and adult neurogenesis. Title: Down-regulation of diacylglycerol lipase-alpha during neural stem cell differentiation: identification of elements that regulate transcription Walker DJ, Suetterlin P, Reisenberg M, Williams G, Doherty P Ref: Journal of Neuroscience Research, 88:735, 2010 : PubMed ESTHER: Walker_2010_J.Neurosci.Res_88_735 PubMedSearch: Walker 2010 J.Neurosci.Res 88 735 PubMedID: 19798744 Abstract The diacylglycerol lipases (DAGLalpha and DAGLbeta) synthesize 2-arachidonoylglycerol (2-AG), a full agonist at cannabinoid receptors. Dynamic regulation of DAGL expression underpins its role in axonal growth and guidance during development, retrograde synaptic signalling at mature synapses, and maintenance of adult neurogenesis. We show here that DAGLalpha expression is dramatically down-regulated when neural stem (NS) cells are differentiated toward a gamma-aminobutyric acidergic neuronal phenotype. To understand how DAGLalpha expression might be controlled, we sought to identify the core promoter region and regulatory elements within it. The core promoter was identified and shown to contain both an enhancer and a suppressor region. Deletion analysis identified two elements, including a GC-box, that specifically promote expression in NS cells. Bioinformatic analysis identified three candidate transcription factors that might regulate DAGLalpha expression in NS cells by binding to the GC box; these were specificity protein 1 (Sp1), early growth response element 1 (EGR1), and zinc finger DNA-binding protein 89 (ZBP-89). However, Sp1 was the only factor that could bind to the GC-box. A specific mutation within the GC-box that inhibited Sp1 binding reduced DAGLalpha promoter activity in NS cells. Likewise, a dominant negative Sp1 was shown to bind to the GC-box and to suppress DAGLalpha promoter activity specifically in NS cells. Finally, like DAGLalpha, Sp1 was down-regulated during neuronal differentiation. A full characterization of the DAGLalpha promoter will help to elucidate the upstream pathways that regulate DAGLalpha expression in NS cells and their progeny. Title: Large scale variation in Enterococcus faecalis illustrated by the genome analysis of strain OG1RF Bourgogne A, Garsin DA, Qin X, Singh KV, Sillanpaa J, Yerrapragada S, Ding Y, Dugan-Rocha S, Buhay C and Weinstock GM <18 more author(s)> Bourgogne A, Garsin DA, Qin X, Singh KV, Sillanpaa J, Yerrapragada S, Ding Y, Dugan-Rocha S, Buhay C, Shen H, Chen G, Williams G, Muzny D, Maadani A, Fox KA, Gioia J, Chen L, Shang Y, Arias CA, Nallapareddy SR, Zhao M, Prakash VP, Chowdhury S, Jiang H, Gibbs RA, Murray BE, Highlander SK, Weinstock GM (- 18) Ref: Genome Biol, 9:R110, 2008 : PubMed ESTHER: Bourgogne_2008_Genome.Biol_9_R110 PubMedSearch: Bourgogne 2008 Genome.Biol 9 R110 PubMedID: 18611278 Gene_locus related to this paper: entfa-EF0101, entfa-EF0449, entfa-EF1236, entfa-EF2618, entfa-q5j1l4, entfl-e2z7d4 Abstract BACKGROUND: Enterococcus faecalis has emerged as a major hospital pathogen. To explore its diversity, we sequenced E. faecalis strain OG1RF, which is commonly used for molecular manipulation and virulence studies. RESULTS: The 2,739,625 base pair chromosome of OG1RF was found to contain approximately 232 kilobases unique to this strain compared to V583, the only publicly available sequenced strain. Almost no mobile genetic elements were found in OG1RF. The 64 areas of divergence were classified into three categories. First, OG1RF carries 39 unique regions, including 2 CRISPR loci and a new WxL locus. Second, we found nine replacements where a sequence specific to V583 was substituted by a sequence specific to OG1RF. For example, the iol operon of OG1RF replaces a possible prophage and the vanB transposon in V583. Finally, we found 16 regions that were present in V583 but missing from OG1RF, including the proposed pathogenicity island, several probable prophages, and the cpsCDEFGHIJK capsular polysaccharide operon. OG1RF was more rapidly but less frequently lethal than V583 in the mouse peritonitis model and considerably outcompeted V583 in a murine model of urinary tract infections. CONCLUSION: E. faecalis OG1RF carries a number of unique loci compared to V583, but the almost complete lack of mobile genetic elements demonstrates that this is not a defining feature of the species. Additionally, OG1RF's effects in experimental models suggest that mediators of virulence may be diverse between different E. faecalis strains and that virulence is not dependent on the presence of mobile genetic elements. Title: A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner Goncalves MB, Suetterlin P, Yip P, Molina-Holgado F, Walker DJ, Oudin MJ, Zentar MP, Pollard S, Yanez-Munoz RJ and Doherty P <3 more author(s)> Goncalves MB, Suetterlin P, Yip P, Molina-Holgado F, Walker DJ, Oudin MJ, Zentar MP, Pollard S, Yanez-Munoz RJ, Williams G, Walsh FS, Pangalos MN, Doherty P (- 3) Ref: Molecular & Cellular Neurosciences, 38:526, 2008 : PubMed ESTHER: Goncalves_2008_Mol.Cell.Neurosci_38_526 PubMedSearch: Goncalves 2008 Mol.Cell.Neurosci 38 526 PubMedID: 18562209 Abstract The subventricular zone (SVZ) is a major site of neurogenesis in the adult. We now show that ependymal and proliferating cells in the adult mouse SVZ express diacylglycerol lipases (DAGLs), enzymes that synthesise a CB1/CB2 cannabinoid receptor ligand. DAGL and CB2 antagonists inhibit the proliferation of cultured neural stem cells, and the proliferation of progenitor cells in young animals. Furthermore, CB2 agonists stimulate progenitor cell proliferation in vivo, with this effect being more pronounced in older animals. A similar response was seen with a fatty acid amide hydrolase (FAAH) inhibitor that limits degradation of endocannabinoids. The effects on proliferation were mirrored in changes in the number of neuroblasts migrating from the SVZ to the olfactory bulb (OB). In this context, CB2 antagonists reduced the number of newborn neurons appearing in the OB in the young adult animals while CB2 agonists stimulated this in older animals. These data identify CB2 receptor agonists and FAAH inhibitors as agents that can counteract the naturally observed decline in adult neurogenesis that is associated with ageing. Title: The DNA sequence of the human X chromosome Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D, Platzer M, Howell GR, Burrows C and Bentley DR <272 more author(s)> Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D, Platzer M, Howell GR, Burrows C, Bird CP, Frankish A, Lovell FL, Howe KL, Ashurst JL, Fulton RS, Sudbrak R, Wen G, Jones MC, Hurles ME, Andrews TD, Scott CE, Searle S, Ramser J, Whittaker A, Deadman R, Carter NP, Hunt SE, Chen R, Cree A, Gunaratne P, Havlak P, Hodgson A, Metzker ML, Richards S, Scott G, Steffen D, Sodergren E, Wheeler DA, Worley KC, Ainscough R, Ambrose KD, Ansari-Lari MA, Aradhya S, Ashwell RI, Babbage AK, Bagguley CL, Ballabio A, Banerjee R, Barker GE, Barlow KF, Barrett IP, Bates KN, Beare DM, Beasley H, Beasley O, Beck A, Bethel G, Blechschmidt K, Brady N, Bray-Allen S, Bridgeman AM, Brown AJ, Brown MJ, Bonnin D, Bruford EA, Buhay C, Burch P, Burford D, Burgess J, Burrill W, Burton J, Bye JM, Carder C, Carrel L, Chako J, Chapman JC, Chavez D, Chen E, Chen G, Chen Y, Chen Z, Chinault C, Ciccodicola A, Clark SY, Clarke G, Clee CM, Clegg S, Clerc-Blankenburg K, Clifford K, Cobley V, Cole CG, Conquer JS, Corby N, Connor RE, David R, Davies J, Davis C, Davis J, Delgado O, Deshazo D, Dhami P, Ding Y, Dinh H, Dodsworth S, Draper H, Dugan-Rocha S, Dunham A, Dunn M, Durbin KJ, Dutta I, Eades T, Ellwood M, Emery-Cohen A, Errington H, Evans KL, Faulkner L, Francis F, Frankland J, Fraser AE, Galgoczy P, Gilbert J, Gill R, Glockner G, Gregory SG, Gribble S, Griffiths C, Grocock R, Gu Y, Gwilliam R, Hamilton C, Hart EA, Hawes A, Heath PD, Heitmann K, Hennig S, Hernandez J, Hinzmann B, Ho S, Hoffs M, Howden PJ, Huckle EJ, Hume J, Hunt PJ, Hunt AR, Isherwood J, Jacob L, Johnson D, Jones S, de Jong PJ, Joseph SS, Keenan S, Kelly S, Kershaw JK, Khan Z, Kioschis P, Klages S, Knights AJ, Kosiura A, Kovar-Smith C, Laird GK, Langford C, Lawlor S, Leversha M, Lewis L, Liu W, Lloyd C, Lloyd DM, Loulseged H, Loveland JE, Lovell JD, Lozado R, Lu J, Lyne R, Ma J, Maheshwari M, Matthews LH, McDowall J, Mclaren S, McMurray A, Meidl P, Meitinger T, Milne S, Miner G, Mistry SL, Morgan M, Morris S, Muller I, Mullikin JC, Nguyen N, Nordsiek G, Nyakatura G, O'Dell CN, Okwuonu G, Palmer S, Pandian R, Parker D, Parrish J, Pasternak S, Patel D, Pearce AV, Pearson DM, Pelan SE, Perez L, Porter KM, Ramsey Y, Reichwald K, Rhodes S, Ridler KA, Schlessinger D, Schueler MG, Sehra HK, Shaw-Smith C, Shen H, Sheridan EM, Shownkeen R, Skuce CD, Smith ML, Sotheran EC, Steingruber HE, Steward CA, Storey R, Swann RM, Swarbreck D, Tabor PE, Taudien S, Taylor T, Teague B, Thomas K, Thorpe A, Timms K, Tracey A, Trevanion S, Tromans AC, d'Urso M, Verduzco D, Villasana D, Waldron L, Wall M, Wang Q, Warren J, Warry GL, Wei X, West A, Whitehead SL, Whiteley MN, Wilkinson JE, Willey DL, Williams G, Williams L, Williamson A, Williamson H, Wilming L, Woodmansey RL, Wray PW, Yen J, Zhang J, Zhou J, Zoghbi H, Zorilla S, Buck D, Reinhardt R, Poustka A, Rosenthal A, Lehrach H, Meindl A, Minx PJ, Hillier LW, Willard HF, Wilson RK, Waterston RH, Rice CM, Vaudin M, Coulson A, Nelson DL, Weinstock G, Sulston JE, Durbin R, Hubbard T, Gibbs RA, Beck S, Rogers J, Bentley DR (- 272) Ref: Nature, 434:325, 2005 : PubMed ESTHER: Ross_2005_Nature_434_325 PubMedSearch: Ross 2005 Nature 434 325 PubMedID: 15772651 Gene_locus related to this paper: human-NLGN3, human-NLGN4X Abstract The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence. Title: Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, Matias I, Schiano-Moriello A, Paul P and Doherty P <4 more author(s)> Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, Matias I, Schiano-Moriello A, Paul P, Williams EJ, Gangadharan U, Hobbs C, Di Marzo V, Doherty P (- 4) Ref: Journal of Cell Biology, 163:463, 2003 : PubMed ESTHER: Bisogno_2003_J.Cell.Biol_163_463 PubMedSearch: Bisogno 2003 J.Cell.Biol 163 463 PubMedID: 14610053 Gene_locus related to this paper: human-DAGLA, human-DAGLB, mouse-DGLB, mouse-q6wqj1 Abstract Diacylglycerol (DAG) lipase activity is required for axonal growth during development and for retrograde synaptic signaling at mature synapses. This enzyme synthesizes the endocannabinoid 2-arachidonoyl-glycerol (2-AG), and the CB1 cannabinoid receptor is also required for the above responses. We now report on the cloning and enzymatic characterization of the first specific sn-1 DAG lipases. Two closely related genes have been identified and their expression in cells correlated with 2-AG biosynthesis and release. The expression of both enzymes changes from axonal tracts in the embryo to dendritic fields in the adult, and this correlates with the developmental change in requirement for 2-AG synthesis from the pre- to the postsynaptic compartment. This switch provides a possible explanation for a fundamental change in endocannabinoid function during brain development. Identification of these enzymes may offer new therapeutic opportunities for a wide range of disorders. | |||||||
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