investigation-synaptic-taggingcapture-cross-capture-using-acute

Investigation of Synaptic Tagging/Capture and Cross-capture using Acute Hippocampal Slices from Rodents

Synaptic tagging and capture (STC) and cross-tagging are two important mechanisms at cellular level that explain how synapse-specificity and associativity ...

National University of Singapore

The CCAAT/enhancer-binding protein alpha (C/EBP alpha) is essential for maintaining the differentiated state of hepatocytes in vivo. C/EBP alpha activates albumin transcription and coordinates the expression of multiple ornithine cycle enzymes involved in urea production. We have examined the effects of the C/EBP alpha knock-in gene on the mRNA and protein expression of genes involved in liver-specific functions, such as albumin and urea production. Albumin mRNA and protein levels are higher in knock-in hepatocytes compared with wild-type hepatocytes. mRNA levels for the ornithine cycle enzymes, namely arginase, carbamylphosphate synthetase 1, and ornithine transcarbamylase, also increase. Albumin secretion and urea production are sustained at higher levels in culture in knock-in hepatocytes. We have previously established that C/EBP alpha induces early liver glycogen storage in C/EBP alpha knock-in mice. Our present observations underline the importance of C/EBP alpha in liver metabolism and suggest that the induction of C/EBP alpha expression enhances hepatocyte function.

C/EBP alpha knock-in hepatocytes exhibit increased albumin secretion and urea production.

SHARP1, a basic helix-loop-helix transcription factor, is expressed in many cell types; however, the mechanisms by which it regulates cellular differentiation remain largely unknown. Here, we show that SHARP1 negatively regulates adipogenesis. Although expression of the early marker CCAAT/enhancer binding protein beta (C/EBPbeta) is not altered, its crucial downstream targets C/EBPalpha and peroxisome proliferator-activated receptor gamma (PPARgamma) are downregulated by SHARP1. Protein interaction studies confirm that SHARP1 interacts with and inhibits the transcriptional activity of both C/EBPbeta and C/EBPalpha, and enhances the association of C/EBPbeta with histone deacetylase 1 (HDAC1). Consistently, in SHARP1-expressing cells, HDAC1 and the histone methyltransferase G9a are retained at the C/EBP regulatory sites on the C/EBPalpha and PPARgamma2 promoters during differentiation, resulting in inhibition of their expression. Interestingly, treatment with troglitazone results in displacement of HDAC1 and G9a, and rescues the differentiation defect of SHARP1-overexpressing cells. Our data indicate that SHARP1 inhibits adipogenesis through the regulation of C/EBP activity, which is essential for PPARgamma-ligand-dependent displacement of co-repressors from adipogenic promoters.

SHARP1/DEC2 inhibits adipogenic differentiation by regulating the activity of C/EBP.

&#xC9C4;&#xBCF4;&#xC801;&#xC778; &#xADFC;&#xC721; &#xC138;&#xD3EC; &#xAD34; &#xC0AC; Duchenne &#xADFC; &#xC704;&#xCD95; &#xC99D; (DMD), dystrophin &#xC190;&#xC2E4;&#xB85C; &#xC778; &#xD55C; &#xD2B9;&#xC9D5;&#xC785;&#xB2C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, DMD&#xC5D0; &#xADFC;&#xC721; &#xBCC0;&#xC131;&#xC73C;&#xB85C; &#xC774;&#xC5B4;&#xC9C0;&#xB294; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC740; &#xC11C; &#xD22C;&#xB974; &#xAC8C; &#xC774;&#xD574;. &#xC5EC;&#xAE30;, &#xC6B0;&#xB9AC; Stra13 &#xC0B0;&#xD654; &#xC190;&#xC0C1; &#xC73C;&#xB85C;&#xBD80;&#xD130; &#xADFC;&#xC721; &#xC138;&#xD3EC;&#xB97C; &#xBCF4;&#xD638; &#xD558; &#xACE0; &#xBD80;&#xC7AC; &#xC751;&#xB2F5; Stra13 &#xACB0;&#xD54D; &#xC0DD;&#xC950;&#xC5D0;&#xC11C; &#xBD80;&#xC0C1;&#xC73C;&#xB85C; &#xADFC;&#xC721; &#xAD34; &#xC0AC; &#xB9AC;&#xB4DC;&#xB97C; &#xBCF4;&#xC5EC; &#xC90D;&#xB2C8;&#xB2E4;. &#xD765;&#xBBF8;&#xB86D;&#xAC8C;&#xB3C4;, Stra13/&#xB3CC;&#xC5F0;&#xBCC0;&#xC774; TNFalpha, heme oxygenase 1&#xC758; &#xAC10;&#xC18C; &#xC218;&#xC900;&#xACFC; &#xADFC;&#xC721; &#xC8FD;&#xC74C; &#xC804;&#xC5D0; &#xC0B0;&#xD654; &#xC2A4;&#xD2B8;&#xB808;&#xC2A4;&#xC758; &#xB514;&#xC2A4;&#xD50C;&#xB808;&#xC774; &#xBA85;&#xBC31;&#xD55C; &#xC9D5;&#xD6C4; &#xB192;&#xC740; &#xC218;&#xC900;&#xC758; &#xD45C;&#xD604;. &#xB610;&#xD55C;, Stra13/&#xADFC;&#xC721; &#xC138;&#xD3EC; &#xD504;&#xB85C; oxidants&#xB97C; &#xC99D;&#xAC00; &#xAC10;&#xB3C4; &#xC804;&#xC2DC; &#xD558; &#xACE0; Stra13 overexpression &#xC0B0;&#xD654; &#xC190;&#xC0C1;&#xC5D0; &#xB300; &#xD55C; &#xC800;&#xD56D;&#xC744; &#xC81C;&#xACF5; &#xD558;&#xB294; &#xBC18;&#xBA74;. &#xC77C;&#xAD00; &#xB418; &#xAC8C;, &#xCE58;&#xB8CC; &#xD53C;&#xBD80; N &#xC9C4; ameliorates Stra13/&#xC950;&#xC5D0;&#xC11C; &#xADFC;&#xC721; &#xAD34; &#xC0AC;. &#xC6B0;&#xB9AC;&#xB294; &#xB610;&#xD55C; Stra13 &#xC2DD; (mdx) dystrophin &#xBD88;&#xCDA9;&#xBD84; &#xD55C; &#xC950;&#xC5D0;&#xC11C; &#xADFC;&#xC721;&#xC5D0; &#xC0C1;&#xC2B9; &#xBC0F; mdx/Stra13 /-&#xB354;&#xBE14; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xC804;&#xC2DC; &#xADFC;&#xC721; &#xBCC0;&#xC131;&#xC758; &#xBC1C;&#xBCD1; &#xCD08;&#xAE30;&#xB97C; &#xBCF4;&#xC5EC; &#xC90D;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xC758; &#xC5F0;&#xAD6C; &#xC0B0;&#xD654; &#xC2A4;&#xD2B8;&#xB808;&#xC2A4; &#xC911;&#xC7AC; &#xADFC;&#xC721; &#xBCC0;&#xC131; &#xADFC; &#xC704;&#xCD95; &#xC99D;&#xC758;&#xC758; &#xC911;&#xC694;&#xC131;&#xC744; &#xAC15;&#xC870; &#xD558; &#xACE0; &#xADFC;&#xC721; &#xBB34;&#xACB0;&#xC131;&#xC758; &#xC720;&#xC9C0; &#xAD00;&#xB9AC;&#xC5D0; stra13&#xC758; &#xAE30;&#xC5EC;&#xB97C; &#xACF5;&#xAC1C; &#xD569;&#xB2C8;&#xB2E4;.

Stra13 &#xC0B0;&#xD654; &#xC2A4;&#xD2B8;&#xB808;&#xC2A4; &#xC911;&#xC7AC; &#xACE8;&#xACA9; &#xADFC;&#xC721; &#xBCC0;&#xC131;&#xC744; &#xC870;&#xC808; &#xD569;&#xB2C8;&#xB2E4;.

&#x5047;&#x80A5;&#x5927;&#x578B;&#x808C;&#x8425;&#x517B;&#x4E0D;&#x826F;&#x75C7; (DMD)&#xFF0C;&#x6240;&#x9020;&#x6210;&#x7684;&#x635F;&#x5931;&#x7684;&#x6297;&#x808C;&#x840E;&#x7F29;&#x86CB;&#x767D;&#x7684;&#x7279;&#x70B9;&#x662F;&#x6E10;&#x8FDB;&#x6027;&#x808C;&#x8089;&#x7EC6;&#x80DE;&#x574F;&#x6B7B;&#x3002;&#x7136;&#x800C;&#xFF0C;&#x5BFC;&#x81F4;&#x5728; DMD &#x808C;&#x8089;&#x53D8;&#x6027;&#x7684;&#x673A;&#x5236;&#x5374;&#x4E0D;&#x751A;&#x4E86;&#x89E3;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x8868;&#x660E;&#x808C;&#x8089;&#x7EC6;&#x80DE;&#x514D;&#x53D7;&#x6C27;&#x5316;&#x635F;&#x4F24;&#xFF0C;Stra13&#xFF0C;&#x5176;&#x7F3A;&#x4E4F;&#x4F1A;&#x5BFC;&#x81F4;&#x808C;&#x8089;&#x574F;&#x6B7B; Stra13 &#x7F3A;&#x9677;&#x5C0F;&#x9F20;&#x635F;&#x4F24;&#x53CD;&#x5E94;&#x4E2D;&#x3002;&#x6709;&#x8DA3;&#x7684;&#x662F;&#xFF0C;Stra13/&#x7A81;&#x53D8;&#x4F53;&#x8868;&#x8FBE;&#x6C34;&#x5E73;&#x5347;&#x9AD8;&#x7684; TNFalpha&#xFF0C;&#x8840;&#x7EA2;&#x7D20;&#x52A0;&#x6C27;&#x9176;-1&#xFF0C;&#x964D;&#x4F4E;&#x6C34;&#x5E73;&#x548C;&#x663E;&#x793A;&#x808C;&#x8089;&#x6B7B;&#x4EA1;&#x4E4B;&#x524D;&#x7684;&#x6C27;&#x5316;&#x5E94;&#x6FC0;&#x7684;&#x660E;&#x663E;&#x8FF9;&#x8C61;&#x3002;&#x6B64;&#x5916;&#xFF0C;Stra13/&#x808C;&#x8089;&#x7EC6;&#x80DE;&#x8868;&#x73B0;&#x51FA;&#x5BF9; pro-&#x6C27;&#x5316;&#x5242;&#xFF0C;&#x589E;&#x52A0;&#x7684;&#x654F;&#x611F;&#x6027;&#xFF0C;&#x76F8;&#x53CD;&#xFF0C;Stra13 &#x8868;&#x8FBE;&#x63D0;&#x4F9B;&#x4E86;&#x6297;&#x6C27;&#x5316;&#x4F5C;&#x7528;&#x3002;&#x59CB;&#x7EC8;&#x5982;&#x4E00;&#xFF0C;&#x6297;&#x6C27;&#x5316;&#x5242; N-&#x4E59;&#x9170;&#x534A;&#x80F1;&#x6C28;&#x9178;&#x6CBB;&#x7597;&#x6539;&#x5584; Stra13/&#x5C0F;&#x9F20;&#x808C;&#x8089;&#x574F;&#x6B7B;&#x3002;&#x6211;&#x4EEC;&#x8FD8;&#x5C55;&#x793A;&#x4E86; Stra13 &#x8868;&#x8FBE;&#x5F0F;&#x5728;&#x808C;&#x8089;&#x9AD8;&#x67B6;&#x4ECE;&#x6297;&#x808C;&#x840E;&#x7F29;&#x86CB;&#x767D;&#x57FA;&#x56E0;&#x7F3A;&#x9677; (mdx) &#x5C0F;&#x9F20;&#xFF0C;&#x5E76;&#x4E14; mdx/Stra13 /-&#x53CC;&#x7A81;&#x53D8;&#x4F53;&#x5C55;&#x793A;&#x808C;&#x8089;&#x53D8;&#x6027;&#x65E9;&#x671F;&#x53D1;&#x75C5;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7814;&#x7A76;&#x5F3A;&#x8C03;&#x7684;&#x6C27;&#x5316;&#x5E94;&#x6FC0;&#x4ECB;&#x5BFC;&#x7684;&#x808C;&#x8089;&#x53D8;&#x6027;&#x808C;&#x8425;&#x517B;&#x4E0D;&#x826F;&#x7684;&#x91CD;&#x8981;&#x6027;&#x548C;&#x63ED;&#x793A;&#x5728;&#x808C;&#x8089;&#x5B8C;&#x6574;&#x6027;&#x7EF4;&#x62A4; Stra13 &#x7684;&#x8D21;&#x732E;&#x3002;

Stra13 &#x89C4;&#x5B9A;&#x4E86;&#x6C27;&#x5316;&#x5E94;&#x6FC0;&#x4ECB;&#x5BFC;&#x7684;&#x9AA8;&#x9ABC;&#x808C;&#x53D8;&#x6027;&#x3002;

Duchenne Muscular Dystrophy (DMD), caused by loss of dystrophin is characterized by progressive muscle cell necrosis. However, the mechanisms leading to muscle degeneration in DMD are poorly understood. Here, we demonstrate that Stra13 protects muscle cells from oxidative damage, and its absence leads to muscle necrosis in response to injury in Stra13-deficient mice. Interestingly, Stra13-/- mutants express elevated levels of TNFalpha, reduced levels of heme-oxygenase-1, and display apparent signs of oxidative stress prior to muscle death. Moreover, Stra13-/- muscle cells exhibit an increased sensitivity to pro-oxidants, and conversely, Stra13 overexpression provides resistance to oxidative damage. Consistently, treatment with anti-oxidant N-acetylcysteine ameliorates muscle necrosis in Stra13-/- mice. We also demonstrate that Stra13 expression is elevated in muscles from dystrophin-deficient (mdx) mice, and mdx/Stra13-/- double mutants exhibit an early onset of muscle degeneration. Our studies underscore the importance of oxidative stress-mediated muscle degeneration in muscular dystrophy, and reveal the contribution of Stra13 in maintenance of muscle integrity.

Stra13 regulates oxidative stress mediated skeletal muscle degeneration.

La dystrophie musculaire de Duchenne (DMD), caus&eacute;e par la perte de la dystrophine est caract&eacute;ris&eacute;e par une n&eacute;crose des cellules musculaires progressives. Cependant, les m&eacute;canismes conduisant &agrave; la d&eacute;g&eacute;n&eacute;rescence musculaire dans DMD sont mal compris. Ici, nous d&eacute;montrons que Stra13 prot&egrave;ge les cellules musculaires des dommages oxydatifs, et son absence conduit &agrave; la n&eacute;crose musculaire en r&eacute;ponse &agrave; des blessures chez les souris d&eacute;ficientes en Stra13. Fait int&eacute;ressant, mutants Stra13-/-expriment des niveaux &eacute;lev&eacute;s de TNFalpha, des niveaux r&eacute;duits de l&#39;h&egrave;me-oxyg&eacute;nase-1 et affichage des signes apparents de stress oxydatif avant la mort de muscle. De plus, Stra13-/-fibres musculaires pr&eacute;sentent une sensibilit&eacute; accrue aux pro-oxydants et inversement, la surexpression de Stra13 offre une r&eacute;sistance aux dommages oxydatifs. Constamment, traitement avec la N-ac&eacute;tylcyst&eacute;ine antioxydant am&eacute;liore la n&eacute;crose musculaire chez les souris Stra13-/. Nous d&eacute;montrons &eacute;galement que Stra13 expression est &eacute;lev&eacute;e dans les muscles de souris d&eacute;ficientes en dystrophine (mdx) et mdx/Stra13-/-double mutants pr&eacute;sentent une d&eacute;g&eacute;n&eacute;rescence musculaire d&#39;apparition pr&eacute;coce. Nos &eacute;tudes soulignent l&#39;importance de la d&eacute;g&eacute;n&eacute;rescence musculaire d&#39;induite par le stress oxydatif dans la dystrophie musculaire et r&eacute;v&egrave;lent la contribution de Stra13 dans le maintien de l&#39;int&eacute;grit&eacute; musculaire.

Stra13 r&eacute;gule la d&eacute;g&eacute;n&eacute;rescence des muscles squelettiques m&eacute;di&eacute;e par le stress oxydatif.

Duchenne-Muskeldystrophie (DMD), verursacht durch Verlust von Dystrophin zeichnet sich durch progressive Muskelentspannung Zelle Nekrose. Allerdings sind die Mechanismen zu Muskel-Degeneration in DMD, schlecht verstanden. Hier zeigen wir, dass Stra13 Muskelzellen vor oxidativen Sch&auml;den sch&uuml;tzt, und sein fehlen zu Muskel Nekrose als Reaktion auf Verletzung in Stra13-defizienten M&auml;usen f&uuml;hrt. Interessanterweise, schnelles Stra13/Mutanten erh&ouml;hte Konzentrationen von TNFalpha, verminderter H&auml;ufigkeit von H&auml;m-Oxygenase-1 und Anzeige offensichtliche Anzeichen f&uuml;r oxidativer Stress vor Muskel Tod. Dar&uuml;ber hinaus Stra13/Muskelzellen weisen eine erh&ouml;hte Empfindlichkeit gegen&uuml;ber Pro-Oxidantien und umgekehrt Stra13 &Uuml;berexpression bietet Widerstand gegen oxidative Sch&auml;den. Konsequent, aerztlichen Behandlung mit anti-oxidant N-Acetylcystein Muskel Nekrose im Stra13-/-M&auml;use. Wir zeigen auch, dass Stra13 Ausdruck Dystrophin-Defizienz (Mdx) M&auml;use in den Muskeln erh&ouml;ht ist und Mdx/Stra13-/-Double Mutanten eine fr&uuml;h beginnende der Muskel-Degeneration weisen. Unsere Studien unterstreichen die Bedeutung der oxidativen Stress-bedingte Muskel-Degeneration in Muskeldystrophie und den Beitrag der Stra13 in der Pflege der Muskel Integrit&auml;t zu offenbaren.

Stra13 regelt oxidativen Stress vermittelte Skelettmuskulatur Entartung.

Distrofia muscolare di Duchenne (DMD), causata dalla perdita della distrofina &egrave; caratterizzata da necrosi cellulare muscolare progressiva. Tuttavia, i meccanismi che portano alla degenerazione muscolare nella DMD sono capiti male. Qui, noi dimostrare che Stra13 protegge le cellule del muscolo dal danno ossidativo, e la sua assenza conduce a necrosi del muscolo in risposta al pregiudizio in mouse Stra13-carenti. &Egrave; interessante notare che, Stra13-/-mutanti esprimono elevati livelli di TNFalpha, livelli ridotti di eme-ossigenasi-1 e display segni evidenti di stress ossidativo prima della morte del muscolo. Inoltre, Stra13-/-muscolo cellule manifestano una maggiore sensibilit&agrave; alla pro-ossidanti, e viceversa, Stra13 sovraespressione fornisce resistenza a danni ossidativi. Coerentemente, trattamento con antiossidante N-acetilcisteina migliora la necrosi muscolare nel Stra13-/-mice. Abbiamo anche dimostrare che Stra13 espressione &egrave; elevata nei muscoli da topi carenti distrofina (mdx) e mdx/Stra13/doppia-mutanti presentano un esordio pi&ugrave; precoce della degenerazione muscolare. I nostri studi sottolineano l&#39;importanza della degenerazione muscolare mediata da stress ossidativo nella distrofia muscolare e rivelano il contributo di Stra13 nel mantenimento dell&#39;integrit&agrave; del muscolo.

Stra13 regola la degenerazione muscolare scheletrico stress ossidativo mediato.

&#x30C7;&#x30E5;&#x30B7;&#x30A7;&#x30F3;&#x30CC;&#x578B;&#x7B4B;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30FC; &#xFF08;DMD&#xFF09;&#x3001;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30F3;&#x306E;&#x640D;&#x5931;&#x306B;&#x3088;&#x3063;&#x3066;&#x5F15;&#x304D;&#x8D77;&#x3053;&#x3055;&#x308C;&#x308B;&#x6F38;&#x9032;&#x7684;&#x7B4B;&#x7D30;&#x80DE;&#x306E;&#x58CA;&#x6B7B;&#x306B;&#x3088;&#x3063;&#x3066;&#x7279;&#x5FB4;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x307E;&#x3059;&#x3002;&#x305F;&#x3060;&#x3057;&#x3001;DMD &#x306E;&#x7B4B;&#x5909;&#x6027;&#x306B;&#x3064;&#x306A;&#x304C;&#x308B;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x306F;&#x3088;&#x304F;&#x308F;&#x304B;&#x3063;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x6211;&#x3005; Stra13 &#x7B4B;&#x7D30;&#x80DE;&#x9178;&#x5316;&#x640D;&#x50B7;&#x304B;&#x3089;&#x4FDD;&#x8B77;&#x3057;&#x3001;&#x305D;&#x306E;&#x4E0D;&#x5728; Stra13 &#x6B20;&#x640D;&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x640D;&#x50B7;&#x306B;&#x5FDC;&#x7B54;&#x3057;&#x3066;&#x7B4B;&#x58CA;&#x6B7B;&#x306B;&#x3064;&#x306A;&#x304C;&#x308B;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x8208;&#x5473;&#x6DF1;&#x3044;&#x3053;&#x3068;&#x306B;&#x3001;Stra13/&#x5909;&#x7570;&#x4F53; TNFalpha &#x306E;&#x30D8;&#x30E0;-&#x30D8;&#x30E0;&#x30AA;&#x30AD;&#x30B7;&#x30B2;&#x30CA;&#x30FC;&#x30BC;-1 &#x306E;&#x6E1B;&#x3089;&#x3055;&#x308C;&#x305F;&#x30EC;&#x30D9;&#x30EB;&#x3068;&#x30C7;&#x30A3;&#x30B9;&#x30D7;&#x30EC;&#x30A4;&#x306E;&#x660E;&#x767D;&#x306A;&#x5146;&#x5019;&#x306E;&#x7B4B;&#x8089;&#x306E;&#x6B7B;&#x306E;&#x524D;&#x306B;&#x9178;&#x5316;&#x30B9;&#x30C8;&#x30EC;&#x30B9;&#x306E;&#x9AD8;&#x3044;&#x30EC;&#x30D9;&#x30EB;&#x3092;&#x8868;&#x73FE;&#x3057;&#x307E;&#x3059;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;pro &#x30AA;&#x30AD;&#x30B7;&#x30C0;&#x30F3;&#x30C8;&#x611F;&#x5EA6; Stra13/&#x7B4B;&#x7D30;&#x80DE;&#x3092;&#x5C55;&#x793A;&#x3057;&#x3001;&#x9006;&#x306B;&#x3001;Stra13 &#x904E;&#x5270;&#x767A;&#x73FE;&#x9178;&#x5316;&#x640D;&#x50B7;&#x3078;&#x306E;&#x62B5;&#x6297;&#x3092;&#x63D0;&#x4F9B;&#x3057;&#x307E;&#x3059;&#x3002;&#x4E00;&#x8CAB;&#x3057;&#x3066;&#x3001;&#x6CBB;&#x7642;&#x3068;&#x6297;&#x9178;&#x5316; N-&#x30A2;&#x30BB;&#x30C1;&#x30EB;&#x30B7;&#x30B9;&#x30C6;&#x30A4;&#x30F3; Stra13/&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x7B4B;&#x58CA;&#x6B7B;&#x306E;&#x6539;&#x5584;&#x3082;&#x3002;&#x6211;&#x3005; &#x306F;&#x307E;&#x305F; Stra13 &#x5F0F;&#x306F;&#x3001;&#x7B4B;&#x8089;&#x306E;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30F3;&#x6B20;&#x640D; (mdx) &#x30DE;&#x30A6;&#x30B9;&#x304B;&#x3089;&#x6607;&#x683C;&#x3055;&#x308C;&#x3001;mdx/Stra13/&#x30C0;&#x30D6;&#x30EB;&#x5909;&#x7570;&#x4F53;&#x7B4B;&#x5909;&#x6027;&#x3092;&#x65E9;&#x671F;&#x306B;&#x767A;&#x75C7;&#x5C55;&#x793A;&#x30C7;&#x30E2;&#x30F3;&#x30B9;&#x30C8;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x3057;&#x307E;&#x3059;&#x3002;&#x79C1;&#x305F;&#x3061;&#x306E;&#x7814;&#x7A76;&#x306F;&#x3001;&#x7B4B;&#x30B8;&#x30B9;&#x30C8;&#x30ED;&#x30D5;&#x30A3;&#x30FC;&#x306E;&#x9178;&#x5316;&#x30B9;&#x30C8;&#x30EC;&#x30B9;&#x3092;&#x4ECB;&#x3057;&#x305F;&#x7B4B;&#x5909;&#x6027;&#x306E;&#x91CD;&#x8981;&#x6027;&#x3092;&#x5F37;&#x8ABF;&#x3057;&#x3066; Stra13 &#x306E;&#x8CA2;&#x732E;&#x306E;&#x30E1;&#x30F3;&#x30C6;&#x30CA;&#x30F3;&#x30B9;&#x7B4B;&#x8089;&#x306E;&#x5B8C;&#x5168;&#x6027;&#x3092;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x307E;&#x3059;&#x3002;

Stra13 &#x3092;&#x4ECB;&#x3057;&#x305F;&#x9178;&#x5316;&#x30B9;&#x30C8;&#x30EC;&#x30B9;&#x9AA8;&#x683C;&#x7B4B;&#x5909;&#x6027;&#x3092;&#x8ABF;&#x7BC0;&#x3057;&#x307E;&#x3059;&#x3002;

Distrofia Muscular de Duchenne (DMD), causada por p&eacute;rdida de distrofina se caracteriza por necrosis muscular progresiva de las c&eacute;lulas. Sin embargo, los mecanismos que conducen a la degeneraci&oacute;n del m&uacute;sculo en DMD se entienden mal. Aqu&iacute;, demostramos que Stra13 protege las c&eacute;lulas del m&uacute;sculo del da&ntilde;o oxidativo, y su ausencia conduce a la necrosis del m&uacute;sculo en respuesta a la lesi&oacute;n en ratones deficientes en Stra13. Curiosamente, Stra13-/-mutantes expresan niveles elevados de TNFalpha, niveles reducidos de hemo-oxigenasa-1 y pantalla evidentes signos de estr&eacute;s oxidativo antes de la muerte del m&uacute;sculo. Adem&aacute;s, las c&eacute;lulas Stra13-/-musculares exhiben una sensibilidad creciente a prooxidantes y por el contrario, la sobreexpresi&oacute;n de Stra13 proporciona resistencia al da&ntilde;o oxidativo. Consistentemente, el tratamiento con N-acetilciste&iacute;na antioxidante mejora la necrosis muscular en Stra13-/-ratones. Tambi&eacute;n demostramos que la expresi&oacute;n de Stra13 se eleva en los m&uacute;sculos de ratones dystrophin-deficientes (mdx), y mdx/Stra13-/-doble mutantes exhiben un inicio temprano de la degeneraci&oacute;n muscular. Nuestros estudios subrayan la importancia de la degeneraci&oacute;n muscular mediada por estr&eacute;s oxidativo en la distrofia muscular y revelan la contribuci&oacute;n de Stra13 en el mantenimiento de la integridad del m&uacute;sculo.

Stra13 regula la degeneraci&oacute;n del m&uacute;sculo esquel&eacute;tico de estr&eacute;s oxidativo mediado.

Skeletal muscle cells have served as a paradigm for understanding mechanisms leading to cellular differentiation. The proliferation and differentiation of muscle precursor cells require the concerted activity of myogenic regulatory factors including MyoD. In addition, chromatin modifiers mediate dynamic modifications of histone tails that are vital to reprogramming cells toward terminal differentiation. Here, we provide evidence for a unique dimension to epigenetic regulation of skeletal myogenesis. We demonstrate that the lysine methyltransferase G9a is dynamically expressed in myoblasts and impedes differentiation in a methyltransferase activity-dependent manner. In addition to mediating histone H3 lysine-9 di-methylation (H3K9me2) on MyoD target promoters, endogenous G9a interacts with MyoD in precursor cells and directly methylates it at lysine 104 (K104) to constrain its transcriptional activity. Mutation of K104 renders MyoD refractory to inhibition by G9a and enhances its myogenic activity. Interestingly, MyoD methylation is critical for G9a-mediated inhibition of myogenesis. These findings provide evidence of an unanticipated role for methyltransferases in cellular differentiation states by direct posttranslational modification of a transcription factor.

Lysine methyltransferase G9a methylates the transcription factor MyoD and regulates skeletal muscle differentiation.

Sharp-1, a basic helix-loop-helix transcription factor, is a potent repressor of skeletal muscle differentiation and is dysregulated in muscle pathologies. However, the mechanisms by which it inhibits myogenesis are not fully understood. Here we show that G9a, a lysine methyltransferase, is involved in Sharp-1-mediated inhibition of muscle differentiation. We demonstrate that G9a directly interacts with Sharp-1 and enhances its ability to transcriptionally repress the myogenin promoter. Concomitant with a differentiation block, G9a-dependent histone H3 lysine 9 dimethylation (H3K9me2) and MyoD methylation are apparent upon Sharp-1 overexpression in muscle cells. RNA interference-mediated reduction of G9a or pharmacological inhibition of its activity erases these repressive marks and rescues the differentiation defect imposed by Sharp-1. Our findings provide new insights into Sharp-1-dependent regulation of myogenesis and identify epigenetic mechanisms that could be targeted in myopathies characterized by elevated Sharp-1 levels.

G9a mediates Sharp-1-dependent inhibition of skeletal muscle differentiation.

Sharp-1 is a basic helix-loop-helix (bHLH) transcriptional repressor that is involved in a number of cellular processes. Our previous studies have demonstrated that Sharp-1 is a negative regulator of skeletal myogenesis and it blocks differentiation of muscle precursor cells by modulating the activity of MyoD. In order to understand its role in pre- and post-natal myogenesis, we assessed skeletal muscle development and freeze-injury-induced regeneration in Sharp-1-deficient mice. We show that embryonic skeletal muscle development is not impaired in the absence of Sharp-1; however, post-natally, the regenerative capacity is compromised. Although the initial phases of injury-induced regeneration proceed normally in Sharp-1(-/-) mice, during late stages, the mutant muscle exhibits necrotic fibers, calcium deposits and fibrosis. TGF-β expression, as well as levels of phosphorylated Smad2 and Smad3, are sustained in the mutant tissue and treatment with decorin, which blocks TGF-β signaling, improves the histopathology of Sharp-1(-/-) injured muscles. In vitro, Sharp-1 associates with Smad3, and its overexpression inhibits TGF-β- and Smad3-mediated expression of extracellular matrix genes in myofibroblasts. These results demonstrate that Sharp-1 regulates muscle regenerative capacity, at least in part, by modulation of TGF-β signaling.

Sharp-1 regulates TGF-β signaling and skeletal muscle regeneration.

Synaptic cooperation and competition are important components of synaptic plasticity that tune synapses for the formation of associative long-term plasticity, a cellular correlate of associative long-term memory. We have recently reported that coincidental activation of weak synapses within the vicinity of potentiated synapses will alter the cooperative state of synapses to a competitive state thus leading to the slow decay of long-term plasticity, but the molecular mechanism underlying this is still unknown. Here, using acute hippocampal slices of rats, we have examined how increasing extracellular dopamine concentrations interact and/or affect electrically induced long-term potentiation (LTP) in the neighboring synapses. We demonstrate that D1/D5-receptor-mediated potentiation at the CA1 Schaffer collateral synapses differentially regulates synaptic co-operation and competition. Further investigating the molecular players involved, we reveal an important role for extracellular signal-regulated kinases-1 and 2 (ERK1/2) as signal integrators and dose-sensors. Interestingly, a sustained activation of ERK1/2 pathway seems to be involved in the differential regulation of synaptic associativity. The concentration-dependent effects of the modulatory transmitter, as demonstrated for dopaminergic signaling in the present study, might offer additional computational power by fine tuning synaptic associativity processes for establishing long-term associative memory in neural networks. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Article	Year
C/EBP alpha knock-in hepatocytes exhibit increased albumin secretion and urea production. Cell and tissue research\| PubMed ID: 17934762	2007
SHARP1/DEC2 inhibits adipogenic differentiation by regulating the activity of C/EBP. EMBO reports\| PubMed ID: 19029947	2009
Stra13 regulates oxidative stress mediated skeletal muscle degeneration. Human molecular genetics\| PubMed ID: 19679564	2009
Lysine methyltransferase G9a methylates the transcription factor MyoD and regulates skeletal muscle differentiation. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 22215600	2012
G9a mediates Sharp-1-dependent inhibition of skeletal muscle differentiation. Molecular biology of the cell\| PubMed ID: 23087213	2012
Sharp-1 regulates TGF-β signaling and skeletal muscle regeneration. Journal of cell science\| PubMed ID: 24357723	2014
Dopamine D1/D5 receptor signaling regulates synaptic cooperation and competition in hippocampal CA1 pyramidal neurons via sustained ERK1/2 activation. Hippocampus\| PubMed ID: 26194339	2015

Suma Gopinadhan

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