precise-cellular-ablation-approach-for-modeling-acute-kidney-injury

Precise Cellular Ablation Approach for Modeling Acute Kidney Injury in Developing Zebrafish

Acute Kidney Injury (AKI) is a common medical condition with a high mortality rate. With the repair abilities of the kidney, it is possible to restore ...

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Nucleoporin Nup98 &#x57FA;&#x56E0;&#x7ECF;&#x5E38;&#x5728;&#x6025;&#x6027;&#x9AD3;&#x7CFB;&#x767D;&#x8840;&#x75C5; (AML) &#x4E2D;&#x91CD;&#x65B0;&#x6392;&#x5217;&#x3002;&#x5728;&#x5927;&#x591A;&#x6570;&#x60C5;&#x51B5;&#x4E0B;&#x8FD9;&#x7ED3;&#x679C;&#x7684; Nup98 N &#x7EC8;&#x70B9;&#x7AD9;&#x878D;&#x5408;&#x5230; homeodomain &#x8F6C;&#x5F55;&#x56E0;&#x5B50;&#x7684; DNA &#x7ED3;&#x5408;&#x57DF;&#x3002;&#x8FD9;&#x4E9B;&#x878D;&#x5408;&#xFF0C;Nup98-HOXA9 &#x7684;&#x539F;&#x578B;&#x662F;&#x4E0E;&#x4EBA;&#x7C7B;&#x53CD;&#x6D17;&#x94B1;&#x76F8;&#x5173;&#x8054;&#x548C;&#x8BF1;&#x5BFC;&#x5C0F;&#x9F20;&#x6A21;&#x578B;&#x4E2D;&#x7684;&#x53CD;&#x6D17;&#x94B1;&#x3002;&#x82E5;&#x8981;&#x4E86;&#x89E3;&#x5176;&#x4E2D; Nup98 HOXA9 &#x5BFC;&#x81F4;&#x53CD;&#x6D17;&#x94B1;&#x7684;&#x673A;&#x5236;&#xFF0C;&#x6211;&#x4EEC;&#x9AD3;&#x7EC6;&#x80DE;&#x8868;&#x8FBE;&#x5B83;&#x548C;&#x786E;&#x5B9A;&#x4F7F;&#x7528;&#x9AD8;&#x5BC6;&#x5EA6;&#x5BE1;&#x6838;&#x82F7;&#x9178;&#x82AF;&#x7247;&#x53CA;&#x5176;&#x9776;&#x57FA;&#x56E0;&#x3002;&#x5206;&#x6790;&#x6267;&#x884C;&#x4E00;&#x5F0F;&#x4E09;&#x4EFD;&#xFF0C;&#x5E76;&#x8BC1;&#x5B9E;&#x4E86;&#x5B9E;&#x65F6;&#x5B9A;&#x91CF; pcr &#x6280;&#x672F;&#x3002;102 Nup98 HOXA9 &#x57FA;&#x56E0;&#x7684;&#x786E;&#x5B9A;&#xFF0C;92 &#x540D;&#x4E0A;&#x8C03;&#xFF0C;&#x548C;&#x53EA;&#x6709; 10 &#x540D;&#x662F;&#x4E0B;&#x8C03;&#xFF0C;&#x8FD9;&#x8868;&#x660E;&#x8F6C;&#x5F55;&#x6FC0;&#x6D3B;&#x529F;&#x80FD;&#x3002;&#x7C7B;&#x4F3C;&#x7684;&#x91CE;&#x751F;&#x578B; HOXA9 &#x7684;&#x5206;&#x6790;&#x63ED;&#x793A; 13 &#x9776;&#x57FA;&#x56E0;&#xFF0C;&#x5176;&#x4E2D; 12 &#x4E2A;&#x662F;&#x4E0A;&#x8C03;&#xFF0C;&#x548C; 1 &#x662F;&#x4E0B;&#x8C03;&#x3002;&#x76F8;&#x6BD4;&#x4E4B;&#x4E0B;&#xFF0C;&#x91CE;&#x751F;&#x578B; Nup98 &#x5DF2;&#x7ECF;&#x4E0D;&#x4F1A;&#x5F71;&#x54CD;&#x57FA;&#x56E0;&#x7684;&#x8868;&#x8FBE;&#xFF0C;&#x8868;&#x660E; HOXA9 DNA &#x7ED3;&#x5408;&#x57DF;&#x57FA;&#x56E0;&#x76D1;&#x7BA1;&#x6240;&#x5FC5;&#x9700;&#x7684;&#x3002;&#x4F7F;&#x7528;&#x94FE;&#x63A5;&#x5230;&#x4E00;&#x4E2A; Nup98 HOXA9 &#x9776;&#x57FA;&#x56E0;&#x7684;&#x542F;&#x52A8;&#x5B50;&#x7684;&#x8367;&#x5149;&#x7D20;&#x9176;&#x62A5;&#x9053;&#x8054;&#x5408;&#x8F6C;&#x67D3;&#x5B9E;&#x9A8C;&#x8BC1;&#x5B9E;&#x7684; Nup98 HOXA9 &#x800C;&#x4E0D;&#x662F;&#x7531; HOXA9 &#x6216; Nup98 &#x8F6C;&#x5F55;&#x4E00;&#x7EA7;&#x4E0A;&#x8C03;&#x3002;&#x8FD9;&#x4E9B;&#x6570;&#x636E;&#x8868;&#x660E; Nup98 HOXA9 &#x5F02;&#x5E38;&#x8F6C;&#x5F55;&#x56E0;&#x5B50;&#x7684;&#x6D3B;&#x52A8;&#x53D6;&#x51B3;&#x4E8E; HOXA9 DNA &#x7ED3;&#x5408;&#x57DF;&#xFF0C;&#x4F46;&#x662F;&#x6709;&#x6BD4; HOXA9 &#x66F4;&#x5F3A;&#x5927;&#x548C;&#x66F4;&#x5E7F;&#x6CDB;&#x8F6C;&#x5F55;&#x7684;&#x5F71;&#x54CD;&#x3002;&#x53D7; Nup98 HOXA9 &#x7684;&#x57FA;&#x56E0;&#x4E2D;&#xFF0C;&#x6709;&#x51E0;&#x4E2A;&#x662F;&#x4E0E;&#x66F4;&#x591A;&#x7684;&#x7EC6;&#x80DE;&#x589E;&#x6B96;&#x548C;&#x751F;&#x5B58;&#xFF0C;&#x4EE5;&#x53CA;&#x836F;&#x7269;&#x4EE3;&#x8C22;&#xFF0C;&#x63D0;&#x4F9B;&#x6DF1;&#x5165;&#x7684;&#x53D1;&#x75C5;&#x673A;&#x5236;&#x53CA;&#x6D41;&#x884C;&#x75C5;&#x5B66;&#x7684; Nup98-HOXA9 &#x8BF1;&#x5BFC;&#x7684;&#x53CD;&#x6D17;&#x94B1;&#x76F8;&#x5173;&#x8054;&#x3002;

Nup98 HOXA9 &#x764C;&#x57FA;&#x56E0;&#x8BF1;&#x5BFC;&#x9AD3;&#x7EC6;&#x80DE;&#x4E2D;&#x7684;&#x57FA;&#x56E0;&#x8F6C;&#x5F55;&#x3002;

The nucleoporin Nup98 gene is frequently rearranged in acute myelogenous leukemia (AML). In most cases this results in fusion of the N terminus of Nup98 to the DNA binding domain of a homeodomain transcription factor. The prototype of these fusions, Nup98-HOXA9, is associated with human AML and induces AML in mouse models. To understand the mechanisms by which Nup98-HOXA9 causes AML, we expressed it in myeloid cells and identified its target genes using high density oligonucleotide microarrays. The analysis was performed in triplicate and was confirmed by quantitative real time PCR. Of the 102 Nup98-HOXA9 target genes identified, 92 were up-regulated, and only 10 were down-regulated, suggesting a transcriptional activation function. A similar analysis of wild-type HOXA9 revealed 13 target genes, 12 of which were up-regulated, and 1 was down-regulated. In contrast, wild-type Nup98 had no effect on gene expression, demonstrating that the HOXA9 DNA binding domain is required for gene regulation. Co-transfection experiments using a luciferase reporter linked to the promoter of one of the Nup98-HOXA9 target genes confirmed up-regulation at the transcriptional level by Nup98-HOXA9 but not by either HOXA9 or Nup98. These data indicate that Nup98-HOXA9 is an aberrant transcription factor whose activity depends on the HOXA9 DNA binding domain but has a stronger and wider transcriptional effect than HOXA9. Several of the genes regulated by Nup98-HOXA9 are associated with increased cell proliferation and survival as well as drug metabolism, providing insights into the pathogenesis and epidemiology of Nup98-HOXA9-induced AML.

The oncogene Nup98-HOXA9 induces gene transcription in myeloid cells.

Le nucl&#xE9;oporine NUP98 g&#xE8;ne est fr&#xE9;quemment r&#xE9;arrang&#xE9;s dans la leuc&#xE9;mie my&#xE9;lo&#xEF;de aigu&#xEB; (LMA). Dans la plupart des cas cela se traduit par la fusion de l&#x26;#39;extr&#xE9;mit&#xE9; N-terminale de la NUP98 au domaine de liaison &#xE0; l&#x26;#39;ADN d&#x26;#39;un facteur de transcription &#xE0; hom&#xE9;odomaine. Le prototype de ces fusions, NUP98-HOXA9, est associ&#xE9; &#xE0; l&#x26;#39;homme AML AML et induit dans des mod&#xE8;les murins. Pour comprendre les m&#xE9;canismes par lesquels NUP98-HoxA9 les causes en mati&#xE8;re de LBC, nous qu&#x26;#39;il a exprim&#xE9;es dans les cellules my&#xE9;lo&#xEF;des et identifi&#xE9; ses g&#xE8;nes cibles &#xE0; l&#x26;#39;aide de haute densit&#xE9; puces &#xE0; oligonucl&#xE9;otides. L&#x26;#39;analyse a &#xE9;t&#xE9; r&#xE9;alis&#xE9;e en trois exemplaires et a &#xE9;t&#xE9; confirm&#xE9; par PCR en temps r&#xE9;el quantitative. Sur les 102 NUP98-HOXA9 g&#xE8;nes cibles identifi&#xE9;s, 92 &#xE9;taient r&#xE9;gul&#xE9;s &#xE0; la hausse, et seulement 10 &#xE9;taient r&#xE9;gul&#xE9;s &#xE0; la baisse, ce qui sugg&#xE8;re une fonction d&#x26;#39;activation transcriptionnelle. Une analyse similaire de type sauvage HOXA9 r&#xE9;v&#xE9;l&#xE9; 13 g&#xE8;nes cibles, dont 12 &#xE9;taient r&#xE9;gul&#xE9;s &#xE0; la hausse, et 1 a &#xE9;t&#xE9; r&#xE9;gul&#xE9;e &#xE0; la baisse. En revanche, de type sauvage NUP98 eu aucun effet sur l&#x26;#39;expression des g&#xE8;nes, ce qui d&#xE9;montre que le domaine HOXA9 liaison &#xE0; l&#x26;#39;ADN est n&#xE9;cessaire pour la r&#xE9;gulation des g&#xE8;nes. Co-transfection des exp&#xE9;riences en utilisant un rapporteur de la lucif&#xE9;rase li&#xE9; au promoteur d&#x26;#39;un des g&#xE8;nes cibles NUP98-HoxA9 confirm&#xE9; up-r&#xE9;gulation au niveau transcriptionnel par NUP98-HOXA9 mais non pas par une HOXA9 ou NUP98. Ces donn&#xE9;es indiquent que NUP98-HOXA9 est un facteur de transcription aberrante dont l&#x26;#39;activit&#xE9; d&#xE9;pend du domaine HOXA9 liaison &#xE0; l&#x26;#39;ADN, mais a un effet plus fort et plus large que la transcription HOXA9. Plusieurs des g&#xE8;nes r&#xE9;gul&#xE9;s par NUP98-HOXA9 sont associ&#xE9;es &#xE0; une prolif&#xE9;ration cellulaire accrue et la survie ainsi que le m&#xE9;tabolisme des m&#xE9;dicaments, apportant des &#xE9;clairages sur la pathogen&#xE8;se et l&#x26;#39;&#xE9;pid&#xE9;miologie de NUP98-HOXA9 induite par la LMA.

L&#x26;#39;oncog&#xE8;ne NUP98-HOXA9 transcription g&#xE9;nique induit dans les cellules my&#xE9;lo&#xEF;des

Das Onkogen Nup98-HoxA9 induziert Gen-Transkription in myeloischen Zellen.

Il gene Nup98 nucleoporin &egrave; spesso riarrangiato in leucemia mieloide acuta (AML). Nella maggior parte dei casi ci&ograve; si traduce in fusione tra il capolinea di N di Nup98 al dominio di associazione del DNA di un fattore di trascrizione homeodomain. Il prototipo di queste fusioni, Nup98-HOXA9, &egrave; associato con AML umana e induce AML in modelli murini. Per comprendere i meccanismi con cui Nup98-HOXA9 cause AML, abbiamo espresso in cellule mieloidi e identificati i geni bersaglio usando i microarrays del oligonucleotide ad alta densit&agrave;. L&#39;analisi &egrave; stata effettuata in triplice copia e fu confermata dal quantitativo PCR in tempo reale. Dei 102 Nup98-HOXA9 obiettivo geni identificati, 92 erano up-regolato, e solo 10 erano down-regolato, suggerendo una funzione di attivazione trascrizionale. Una simile analisi del selvaggio-tipo HOXA9 rivelato 13 geni bersaglio, 12 delle quali sono state up-regolato, e 1 era gi&ugrave;-regolato. Al contrario, selvaggio-tipo Nup98 ha avuto alcun effetto sull&#39;espressione del gene, dimostrando che il dominio di legame del DNA HOXA9 &egrave; necessario per la regolazione dei geni. Esperimenti di co-transfection usando un reporter di luciferase legato al promotore di uno dei geni target Nup98-HOXA9 confermato su-regolazione a livello trascrizionale di Nup98-HOXA9, ma non da HOXA9 o Nup98. Questi dati indicano che Nup98-HOXA9 &egrave; un fattore di trascrizione aberranti cui attivit&agrave; dipende dal dominio di legame del DNA HOXA9 ma ha un effetto pi&ugrave; forte e pi&ugrave; ampia transcriptional rispetto HOXA9. Molti dei geni regolati da Nup98-HOXA9 sono associati con aumento della proliferazione cellulare e sopravvivenza cos&igrave; come il metabolismo del farmaco, fornendo approfondimenti la patogenesi ed epidemiologia di AML Nup98-HOXA9-indotta.

L&#39;oncogene Nup98-HOXA9 induce la trascrizione del gene in cellule mieloidi.

&#x30CC;&#x30AF;&#x30EC;&#x30AA;&#x30DD;&#x30EA;&#x30F3;NUP98&#x907A;&#x4F1D;&#x5B50;&#x306F;&#x3001;&#x3057;&#x3070;&#x3057;&#x3070;&#x6025;&#x6027;&#x9AA8;&#x9AC4;&#x6027;&#x767D;&#x8840;&#x75C5;&#xFF08;AML&#xFF09;&#x306B;&#x518D;&#x914D;&#x7F6E;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x30DB;&#x30E1;&#x30AA;&#x30C9;&#x30E1;&#x30A4;&#x30F3;&#x8EE2;&#x5199;&#x56E0;&#x5B50;&#x306E;DNA&#x7D50;&#x5408;&#x30C9;&#x30E1;&#x30A4;&#x30F3;&#x306B;NUP98&#x306E;N&#x672B;&#x7AEF;&#x306E;&#x878D;&#x5408;&#x3067;&#x3001;&#x307B;&#x3068;&#x3093;&#x3069;&#x306E;&#x5834;&#x5408;&#x3001;&#x3053;&#x306E;&#x7D50;&#x679C;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x878D;&#x5408;&#x306E;&#x30D7;&#x30ED;&#x30C8;&#x30BF;&#x30A4;&#x30D7;&#x3001;NUP98-HOXA9&#x306F;&#x3001;&#x30DE;&#x30A6;&#x30B9;&#x30E2;&#x30C7;&#x30EB;&#x3067;&#x30D2;&#x30C8;AML&#x3068;&#x3092;&#x8A98;&#x5C0E;AML&#x306B;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x306B;&#x3088;&#x3063;&#x3066;NUP98-HOXA9&#x306E;&#x539F;&#x56E0;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;AML&#x3092;&#x7406;&#x89E3;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x3001;&#x6211;&#x3005;&#x306F;&#x9AA8;&#x9AC4;&#x7D30;&#x80DE;&#x306B;&#x305D;&#x308C;&#x3092;&#x8868;&#x660E;&#x3057;&#x3001;&#x9AD8;&#x5BC6;&#x5EA6;&#x30AA;&#x30EA;&#x30B4;&#x30CC;&#x30AF;&#x30EC;&#x30AA;&#x30C1;&#x30C9;&#x30DE;&#x30A4;&#x30AF;&#x30ED;&#x30A2;&#x30EC;&#x30A4;&#x3092;&#x7528;&#x3044;&#x3066;&#x305D;&#x306E;&#x6A19;&#x7684;&#x907A;&#x4F1D;&#x5B50;&#x3092;&#x540C;&#x5B9A;&#x3057;&#x305F;&#x3002;&#x5206;&#x6790;&#x306F;&#x4E09;&#x91CD;&#x3067;&#x884C;&#x308F;&#x308C;&#x305F;&#x3068;&#x5B9A;&#x91CF;&#x7684;&#x30EA;&#x30A2;&#x30EB;&#x30BF;&#x30A4;&#x30E0;PCR&#x306B;&#x3088;&#x308A;&#x78BA;&#x8A8D;&#x3057;&#x305F;&#x3002;&#x8B58;&#x5225;102 NUP98-HOXA9&#x306E;&#x6A19;&#x7684;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x3046;&#x3061;&#x3001;92&#x306F;&#x30A2;&#x30C3;&#x30D7;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30C8;&#x3057;&#x305F;&#x3001;&#x552F;&#x4E00;&#x306E;10&#x306F;&#x3001;&#x30C0;&#x30A6;&#x30F3;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30C8;&#x3057;&#x305F;&#x3001;&#x8EE2;&#x5199;&#x6D3B;&#x6027;&#x5316;&#x6A5F;&#x80FD;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;&#x91CE;&#x751F;&#x578B;HOXA9&#x306E;&#x540C;&#x69D8;&#x306E;&#x5206;&#x6790;&#x306F;&#x3001;&#x30A2;&#x30C3;&#x30D7;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30C8;&#x3055;&#x308C;&#x3001;1&#x304C;&#x30C0;&#x30A6;&#x30F3;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30C8;&#x3057;&#x305F;12&#x305D;&#x306E;&#x3046;&#x3061;&#x3001;13&#x306E;&#x6A19;&#x7684;&#x907A;&#x4F1D;&#x5B50;&#x3092;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x305F;&#x3002;&#x5BFE;&#x7167;&#x7684;&#x306B;&#x3001;&#x91CE;&#x751F;&#x578B;NUP98&#x306F;HOXA9 DNA&#x7D50;&#x5408;&#x30C9;&#x30E1;&#x30A4;&#x30F3;&#x306F;&#x907A;&#x4F1D;&#x5B50;&#x767A;&#x73FE;&#x5236;&#x5FA1;&#x306B;&#x5FC5;&#x8981;&#x3068;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x3053;&#x3068;&#x3092;&#x5B9F;&#x8A3C;&#x3057;&#x3001;&#x907A;&#x4F1D;&#x5B50;&#x767A;&#x73FE;&#x306B;&#x5F71;&#x97FF;&#x3092;&#x200B;&#x200B;&#x53CA;&#x307C;&#x3055;&#x306A;&#x304B;&#x3063;&#x305F;&#x3002; NUP98-HOXA9&#x6A19;&#x7684;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x4E00;&#x3064;&#x306E;&#x30D7;&#x30ED;&#x30E2;&#x30FC;&#x30BF;&#x30FC;&#x306B;&#x9023;&#x7D50;&#x3055;&#x308C;&#x305F;&#x30EB;&#x30B7;&#x30D5;&#x30A7;&#x30E9;&#x30FC;&#x30BC;&#x30EC;&#x30DD;&#x30FC;&#x30BF;&#x30FC;&#x3092;&#x7528;&#x3044;&#x305F;&#x5171;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30D5;&#x30A7;&#x30AF;&#x30B7;&#x30E7;&#x30F3;&#x5B9F;&#x9A13;&#x3067;&#x306F;&#x306A;&#x304F;&#x3001;HOXA9&#x307E;&#x305F;&#x306F;NUP98&#x306E;&#x3044;&#x305A;&#x308C;&#x304B;&#x306B;&#x3088;&#x3063;&#x3066;NUP98-HOXA9&#x306B;&#x3088;&#x308B;&#x8EE2;&#x5199;&#x30EC;&#x30D9;&#x30EB;&#x3067;&#x306E;&#x30A2;&#x30C3;&#x30D7;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x3092;&#x78BA;&#x8A8D;&#x3057;&#x305F;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x30C7;&#x30FC;&#x30BF;&#x306F;&#x3001;NUP98-HOXA9&#x306F;&#x3001;&#x305D;&#x306E;&#x6D3B;&#x52D5;HOXA9 DNA&#x7D50;&#x5408;&#x30C9;&#x30E1;&#x30A4;&#x30F3;&#x306B;&#x4F9D;&#x5B58;&#x3059;&#x308B;&#x304C;&#x3001;HOXA9&#x3088;&#x308A;&#x5F37;&#x304F;&#x3001;&#x3088;&#x308A;&#x5E83;&#x3044;&#x8EE2;&#x5199;&#x52B9;&#x679C;&#x3092;&#x6301;&#x3063;&#x3066;&#x3044;&#x308B;&#x7570;&#x5E38;&#x306A;&#x8EE2;&#x5199;&#x56E0;&#x5B50;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002; NUP98-HOXA9&#x306B;&#x3088;&#x308A;&#x8ABF;&#x7BC0;&#x3055;&#x308C;&#x308B;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x3044;&#x304F;&#x3064;&#x304B;&#x306F;&#x3001;NUP98-HOXA9&#x8A98;&#x767A;&#x6027;&#x6025;&#x6027;&#x9AA8;&#x9AC4;&#x6027;&#x767D;&#x8840;&#x75C5;&#x306E;&#x75C5;&#x56E0;&#x3068;&#x75AB;&#x5B66;&#x3078;&#x306E;&#x6D1E;&#x5BDF;&#x3092;&#x63D0;&#x4F9B;&#x3057;&#x3001;&#x5897;&#x52A0;&#x3057;&#x305F;&#x7D30;&#x80DE;&#x306E;&#x5897;&#x6B96;&#x304A;&#x3088;&#x3073;&#x751F;&#x5B58;&#x3068;&#x540C;&#x69D8;&#x306B;&#x85AC;&#x7269;&#x4EE3;&#x8B1D;&#x306B;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

&#x764C;&#x907A;&#x4F1D;&#x5B50;NUP98-HOXA9&#x306F;&#x3001;&#x9AA8;&#x9AC4;&#x7D30;&#x80DE;&#x306B;&#x304A;&#x3051;&#x308B;&#x907A;&#x4F1D;&#x5B50;&#x8EE2;&#x5199;&#x3092;&#x8A98;&#x5C0E;&#x3059;&#x308B;

Nucleoporin Nup98 &#xC9C4; &#xC790;&#xC8FC; &#xAE09;&#xC131; &#xACE8;&#xC218;&#xC131; &#xBC31;&#xD608;&#xBCD1; (AML)&#xC5D0; &#xB2E4;&#xC2DC; &#xC815;&#xB82C; &#xD569;&#xB2C8;&#xB2E4;. &#xB300;&#xBD80;&#xBD84;&#xC758; &#xACBD;&#xC6B0;&#xC774; homeodomain &#xC804;&#xC0AC; &#xC778;&#xC790;&#xB294; DNA &#xBC14;&#xC778;&#xB529; &#xB3C4;&#xBA54;&#xC778;&#xC744; nup98&#xC758; N &#xB9D0;&#xB2E8;&#xC758; &#xC735;&#xD569; &#xACB0;&#xACFC;. &#xC774;&#xB7EC;&#xD55C; fusions Nup98 hoxa9&#xC758; &#xD504;&#xB85C;&#xD1A0; &#xD0C0;&#xC785; &#xC778;&#xAC04;&#xC758; AML &#xC5F0;&#xACB0; &#xB418;&#xBA70; &#xB9C8;&#xC6B0;&#xC2A4; &#xBAA8;&#xB378;&#xC5D0;&#xC11C; AML&#xC744; &#xC720;&#xB3C4; &#xD55C;&#xB2E4;. Nup98-hoxa9&#xB294; &#xAE09;&#xC131; &#xACE8;&#xC218;&#xC131; &#xBC31;&#xD608;&#xBCD1; &#xBC1C;&#xC0DD; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xC774;&#xD574; &#xD558;&#xAE30; &#xC6B0;&#xB9AC; &#xACE8;&#xC218;&#xC131; &#xC138;&#xD3EC; &#xD45C;&#xD604; &#xB418; &#xACE0; &#xACE0;&#xBC00;&#xB3C4; oligonucleotide microarrays&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xB300;&#xC0C1; &#xC720;&#xC804;&#xC790;&#xC758; &#xC2DD;&#xBCC4;. &#xBD84;&#xC11D;&#xACFC; 3 &#xC911;&#xC5D0; &#xC218;&#xD589; &#xB41C; &#xC815;&#xB7C9;&#xC801; &#xC2E4;&#xC2DC;&#xAC04; PCR&#xC5D0; &#xC758;&#xD574; &#xD655;&#xC778; &#xB418;&#xC5C8;&#xB2E4;. 102 Nup98 HOXA9 &#xB300;&#xC0C1; &#xC720;&#xC804;&#xC790;&#xB97C; &#xC2DD;&#xBCC4;&#xC758; 92 &#xD588;&#xB2E4; &#xCD5C;&#xB300; &#xD1B5;&#xC81C; &#xD558; &#xACE0; &#xC720;&#xC77C;&#xD55C; 10 &#xB2E4;&#xC6B4; &#xADDC;&#xC81C;, transcriptional &#xD65C;&#xC131;&#xD654; &#xD568;&#xC218;&#xB97C; &#xC81C;&#xC548; &#xD588;&#xB2E4;. &#xC57C;&#xC0DD;-&#xD0C0;&#xC785; hoxa9&#xC5D0; &#xB300; &#xD55C; &#xC720;&#xC0AC;&#xD55C; &#xBD84;&#xC11D; 13 &#xB300;&#xC0C1; &#xC720;&#xC804;&#xC790;&#xB294; 12 &#xC704;&#xB85C; &#xD588;&#xB2E4;, &#xADF8;&#xB9AC;&#xACE0; 1&#xC740; &#xC544;&#xB798;&#xB85C;. &#xBC18;&#xBA74;, &#xC57C;&#xC0DD;-&#xD0C0;&#xC785; Nup98 &#xD588;&#xB2E4; HOXA9 DNA &#xBC14;&#xC778;&#xB529; &#xB3C4;&#xBA54;&#xC778; &#xC720;&#xC804;&#xC790; &#xC870;&#xC808;&#xC5D0; &#xB300; &#xD55C; &#xD544;&#xC694; &#xD558;&#xB2E4;&#xB294; &#xAC83;&#xC744; &#xBCF4;&#xC5EC;&#xC8FC;&#xB294; &#xC720;&#xC804;&#xC790; &#xBC1C;&#xD604;&#xC5D0; &#xC601;&#xD5A5;&#xC744; &#xC8FC;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4;. &#xB8E8;&#xC2DC;&#xD398;&#xB77C;&#xC544;&#xC81C; &#xAE30;&#xC790; Nup98 HOXA9 &#xB300;&#xC0C1; &#xC720;&#xC804;&#xC790;&#xC758; &#xD504;&#xB85C;&#xBAA8;&#xD130;&#xC5D0; &#xC5F0;&#xACB0;&#xC744; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; co-transfection &#xC2E4;&#xD5D8; &#xD655;&#xC778; &#xCD5C;&#xB300;-&#xB808; &#xADE4; &#xB808;&#xC774; &#xC158; HOXA9 &#xB610;&#xB294; Nup98 &#xC544;&#xB2C8;&#xB77C; Nup98 hoxa9&#xC5D0; &#xC758;&#xD574; transcriptional &#xC218;&#xC900;. &#xC774;&#xB7EC;&#xD55C; &#xB370;&#xC774;&#xD130; Nup98 HOXA9 &#xB204;&#xAD6C;&#xC758; &#xD65C;&#xB3D9; HOXA9 DNA &#xBC14;&#xC778;&#xB529; &#xB3C4;&#xBA54;&#xC778;&#xC5D0; &#xB530;&#xB77C; &#xB2EC;&#xB77C; &#xC9D1;&#xB2C8;&#xB2E4; &#xC788;&#xC9C0;&#xB9CC; HOXA9 &#xBCF4;&#xB2E4; &#xB354; &#xAC15;&#xD558;&#xACE0; &#xB113;&#xC740; transcriptional &#xD6A8;&#xACFC;&#xAC00; &#xD0C8; &#xC120; &#xC804;&#xC0AC; &#xC694;&#xC18C;&#xAC00; &#xC788;&#xC74C;&#xC744; &#xB098;&#xD0C0;&#xB0C5;&#xB2C8;&#xB2E4;. Nup98 hoxa9&#xC5D0; &#xC758;&#xD574; &#xADDC;&#xC81C; &#xD558;&#xB294; &#xC720;&#xC804;&#xC790;&#xC758; &#xC77C;&#xBD80; &#xC99D;&#xAC00; &#xC138;&#xD3EC; &#xC99D;&#xC2DD;&#xACFC; &#xC0DD;&#xC874; &#xBFD0;&#xB9CC; &#xC544;&#xB2C8;&#xB77C; &#xC57D;&#xBB3C; &#xB300;&#xC0AC;, pathogenesis &#xBC0F; Nup98 HOXA9 &#xC720;&#xBC1C; &#xB41C; &#xAE09;&#xC131; &#xACE8;&#xC218;&#xC131; &#xBC31;&#xD608;&#xBCD1;&#xC758; &#xC5ED;&#xD559;&#xC5D0; &#xB300; &#xD55C; &#xD1B5;&#xCC30;&#xB825;&#xC744; &#xC81C;&#xACF5; &#xD558; &#xACE0; &#xC5F0;&#xACB0; &#xB429;&#xB2C8;&#xB2E4;.

Nup98 HOXA9 oncogene &#xACE8;&#xC218;&#xC131; &#xC138;&#xD3EC;&#xC5D0;&#xC11C; &#xC720;&#xC804;&#xC790; &#xC804;&#xC0AC;&#xB97C; &#xC720;&#xB3C4;&#xD569;&#xB2C8;&#xB2E4;.

El nucleoporin Nup98 gen a menudo se reorganizan en la leucemia miel&#xF3;gena aguda (LMA). En la mayor&#xED;a de los casos esto da como resultado la fusi&#xF3;n del extremo N de Nup98 al dominio de uni&#xF3;n al ADN de un factor de transcripci&#xF3;n homeodominio. El prototipo de estas fusiones, Nup98-Hoxa9, se asocia con la LMA y LMA humana induce en modelos de rat&#xF3;n. Para comprender los mecanismos por los cuales Nup98-Hoxa9 causa de la LMA, que se expresan en c&#xE9;lulas mieloides y se identificaron sus genes diana con alta densidad de microarrays de ADN. El an&#xE1;lisis se realiz&#xF3; por triplicado y fue confirmado por PCR cuantitativa en tiempo real. De los 102 Nup98-Hoxa9 genes diana identificados, 92 fueron reguladas, y s&#xF3;lo el 10 se redujeron regulado, lo que sugiere una funci&#xF3;n de activaci&#xF3;n de la transcripci&#xF3;n. Un an&#xE1;lisis similar de tipo salvaje Hoxa9 revel&#xF3; 13 genes diana, 12 de los cuales fueron hasta reguladas, y 1 era el regulado. En contraste, de tipo salvaje Nup98 no tuvo ning&#xFA;n efecto sobre la expresi&#xF3;n g&#xE9;nica, lo que demuestra que el dominio de uni&#xF3;n ADN Hoxa9 se requiere para la regulaci&#xF3;n de genes. Co-transfecci&#xF3;n experimentos utilizando un reportero de la luciferasa unido al promotor de uno de los genes diana Nup98-Hoxa9 confirm&#xF3; la regulaci&#xF3;n a nivel transcripcional por Nup98 Hoxa9-pero no por cualquiera de las Hoxa9 o Nup98. Estos datos indican que Nup98-Hoxa9 es un factor de transcripci&#xF3;n aberrante cuya actividad depende del dominio de ADN Hoxa9 vinculante, pero tiene un efecto fuerte y m&#xE1;s amplia de la transcripci&#xF3;n de Hoxa9. Varios de los genes regulados por Nup98-Hoxa9 se asocian con aumento de la proliferaci&#xF3;n celular y la supervivencia, as&#xED; como el metabolismo de f&#xE1;rmacos, y proporciona informaci&#xF3;n sobre la patog&#xE9;nesis y la epidemiolog&#xED;a de Nup98-Hoxa9 LMA inducida.

El oncog&#xE9;n Nup98-Hoxa9 induce la transcripci&#xF3;n de genes en las c&#xE9;lulas mieloides

The T-domain transcription factors, Tbx5 and Tbx4, play important roles in vertebrate limb and heart development. To identify interacting and potential Tbx-regulating proteins, we performed a yeast two-hybrid screen with the C-terminal domain of Tbx5 as bait. We identified a new PDZ-LIM protein composed of one N-terminal PDZ and three C-terminal LIM domains, which we named chicken LMP-4. Among the Tbx2, 3, 4, 5 subfamily, we observed exclusive interaction with Tbx5 and Tbx4 proteins. Tbx3 nor Tbx2 can substitute for LMP-4 binding. While chicken LMP-4 associates with Tbx5 or Tbx4, it uses distinct LIM domains to bind to the individual proteins. Subcellular co-localization of LMP-4 and Tbx proteins supports the protein interaction and reveals interference of LMP-4 with Tbx protein distribution, tethering the transcription factors to the cytoskeleton. The protein-protein interaction indicates regulation of Tbx function at the level of transcription factor nuclear localization. During chicken limb and heart development, Tbx5/LMP-4 and Tbx4/LMP-4 are tightly co-expressed in a temporal and spatial manner, suggesting that they operate in the same pathway. Surprisingly, chicken LMP-4 expression domains outside those of Tbx5 in the heart led to the discovery of Tbx4 expression in the outflow tract and the right ventricle of this organ. The Tbx4-expressing cells coincide with those of the recently discovered secondary anterior heart-forming field. The discrete posterior or anterior expression domains in the heart and the exclusive fore- or hindlimb expression of Tbx5 and Tbx4, respectively, suggest common pathways in the heart and limbs. The identification of a new Tbx5/4-specific binding factor further suggests a novel mechanism for Tbx transcription factor regulation in development and disease.

Tbx5 and Tbx4 transcription factors interact with a new chicken PDZ-LIM protein in limb and heart development.

The limb- and heart-specific Tbx5 transcription factor coexpresses with and directly binds to the novel PDZ-LIM domain protein, LMP4. LMP4 is distributed in the cytoplasm associated with the actin cytoskeleton. In the presence of LMP4, Tbx5 shuttles dynamically between the nucleus and cytoplasm and, in a complex with LMP4, localizes to actin filaments. Nuclear and cytoplasmic Tbx5 distribution in developing chicken wings suggests the functional significance of the LMP4-Tbx5 interaction. In primary epicardial cells, we demonstrate that Tbx5 protein subcellular relocalization can be stimulated by external signals that induce cell differentiation. To test whether the relocalization from nuclear to cytoplasmic sites interferes with downstream gene expression, we used limb-specific Fgf10 and heart-specific Anf promoter-luciferase reporters and demonstrate that LMP4 acts as a repressor of Tbx5 activity. These studies reveal a previously unknown mechanism for Tbx transcription factor regulation in vertebrate limb and heart development and provide a better understanding of the molecular basis of hand/heart birth defects associated with Tbx5 mutations.

LMP4 regulates Tbx5 protein subcellular localization and activity.

&#xADF8;&#xB7EC;&#xB098; tbx5&#xB294; &#xC120; &#xCC9C; &#xC131; &#xC2EC;&#xC7A5; &#xC9C8;&#xD658;&#xC5D0; &#xAD00;&#xC5EC;,, &#xC7A5;&#xAE30; &#xAE30;&#xD615; &#xC120;&#xB3C4; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC740; &#xD06C;&#xAC8C; &#xC54C;&#xB824;&#xC9C4;. &#xC6B0;&#xB9AC;&#xB294; Tbx5 &#xBC14;&#xC778;&#xB529; &#xB2E8;&#xBC31;&#xC9C8; Pdlim7 &#xD575;/&#xC138;&#xD3EC;&#xC9C8; &#xC600;&#xC8E0; &#xBC0F; &#xB179;&#xC74C; &#xBC29;&#xC1A1; &#xC694;&#xC778;&#xC758; &#xAE30;&#xB2A5;&#xC744; &#xC81C;&#xC5B4; &#xD558;&#xB294; &#xBAA8;&#xB378; &#xAC00;&#xC124;&#xC744; &#xC138;&#xC6E0;&#xB2E4;. &#xC2EC;&#xC7A5; &#xD615;&#xC131;&#xC758; &#xADDC;&#xC815;&#xC5D0;&#xC11C; Tbx5/Pdlim7 &#xB2E8;&#xBC31;&#xC9C8; &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC758; &#xC911;&#xC694; &#xD55C; &#xC5ED;&#xD560;&#xC5D0; &#xB300; &#xD55C; vivo&#xC5D0;&#xC11C; &#xC758;&#xBBF8; &#xC120;&#xBB3C;&#xC774; &#xB41C; zebrafish&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC;. &#xBE44; &#xBC18;&#xBCF5; &#xB9C8;&#xC74C;&#xC744; &#xAE30; &#xB9C9;&#xD788;&#xAC8C; tbx5 &#xC2EC; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xD45C;&#xD604; &#xD615;&#xC758; &#xC5F0;&#xC0C1;&#xC5D0;&#xC11C; Pdlim7 &#xACB0;&#xACFC;&#xC758; &#xB179; &#xB2E4;&#xC6B4;. &#xADF8;&#xB7EC;&#xB098;, &#xB3D9;&#xC548; misregulation pdlim7&#xC640; tbx5&#xC758; &#xC0DD;&#xC0B0; &#xC720;&#xC0AC;&#xD55C; &#xD0C8; &#xC120; &#xC2EC;&#xC7A5; &#xD615;&#xD0DC;&#xD559;, &#xBD84;&#xC790; &#xBC0F; &#xC870;&#xC9C1;&#xD559; &#xBD84;&#xC11D; Pdlim7 &#xBC0F; Tbx5 &#xC2EC;&#xC7A5; &#xACE0;&#xAE30; &#xB54C;&#xBB38;&#xC5D0; &#xBC38;&#xBE0C; &#xAC1C;&#xBC1C;&#xC5D0; &#xB300; &#xD55C; &#xBC18;&#xB300; &#xD6A8;&#xACFC; &#xBC1C;&#xACAC; &#xD588;&#xB2E4;. Pdlim7 &#xAE30;&#xB2A5;&#xC758; &#xC190;&#xC2E4; &#xBC1C;&#xC0DD; &#xBD80;&#xC871;&#xC758; &#xC99D;&#xAC00; &#xBC38;&#xBE0C; &#xC870;&#xC9C1;&#xC5D0;&#xC11C; Tbx5 &#xAC80;&#xC0C9; &#xD558;&#xB294; &#xB3D9;&#xC548; &#xAC1C;&#xBC1C; &#xBC38;&#xBE0C; &#xC870;&#xC9C1; &#xC544;&#xB2C8;. &#xC774;&#xB7EC;&#xD55C; &#xBC18;&#xB300; &#xACB0;&#xD568;&#xACFC; &#xBC38;&#xBE0C; &#xD615;&#xC131; &#xD558;&#xAE30; &#xC804;&#xC5D0; &#xBD84;&#xBA85; atrio &#xC2EC; &#xC2E4; (AV) &#xACBD;&#xACC4;&#xC758; &#xC0AC;&#xC591; &#xC911; &#xACE0;&#xC720; &#xC720;&#xC804;&#xC790; misregulation&#xC758; &#xACB0;&#xACFC;&#xC785;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; Pdlim7/Tbx5 &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC5D0; &#xC601;&#xD5A5;&#xC744; Tbx5 &#xB300;&#xC0C1; &#xC720;&#xC804;&#xC790; nppa &#xBC0F; AV &#xACBD;&#xACC4;&#xC5D0;&#xC11C; tbx2b&#xC758; &#xC2DD; misexpression&#xC758; &#xADF8;&#xB4E4;&#xC758; &#xB3C4;&#xBA54;&#xC778;&#xC744; &#xC9C1;&#xC811; &#xD655;&#xC778; &#xB41C; &#xBC38;&#xBE0C; &#xACB0;&#xD568; &#xC5F0;&#xAD00; &#xD45C;&#xC2DC;. &#xC774;&#xB7EC;&#xD55C; &#xC5F0;&#xAD6C; Tbx5 &#xD65C;&#xB3D9;&#xC758; &#xC62C;&#xBC14;&#xB978; &#xADE0;&#xD615;&#xC744; &#xC81C;&#xC5B4; AV &#xACBD;&#xACC4;&#xC640; &#xBC38;&#xBE0C; &#xD615;&#xC131;&#xC758; &#xC0AC;&#xC591;&#xC5D0; &#xB300; &#xD55C; &#xC911;&#xC694; &#xD558;&#xB2E4;&#xB294; &#xC124;&#xBA85;.

Pdlim7 (LMP4) &#xB808; &#xADE4; &#xB808;&#xC774; &#xC158; tbx5&#xC758; &#xC9C0;&#xC815; zebrafish &#xC2EC;&#xC7A5; atrio &#xC2EC; &#xC2E4; &#xACBD;&#xACC4;&#xC640; &#xBC38;&#xBE0C; &#xD615;&#xC131;.

Tbx5 &#x6D89;&#x53CA;&#x7684;&#x5148;&#x5929;&#x6027;&#x5FC3;&#x810F;&#x75C5;&#xFF0C;&#x4F46;&#x662F;&#xFF0C;&#x5BFC;&#x81F4;&#x5668;&#x5B98;&#x7578;&#x5F62;&#x7684;&#x673A;&#x5236;&#x6781;&#x5927;&#x5730;&#x672A;&#x77E5;&#x3002;&#x6211;&#x4EEC;&#x5047;&#x8BBE;&#x5176;&#x4E2D; Tbx5 &#x7ED3;&#x5408;&#x86CB;&#x767D; Pdlim7 &#x63A7;&#x5236;&#x6838;/&#x7EC6;&#x80DE;&#x8D28;&#x7A7F;&#x68AD;&#x548C;&#x8F6C;&#x5F55;&#x56E0;&#x5B50;&#x7684;&#x529F;&#x80FD;&#x6A21;&#x578B;&#x3002;&#x6211;&#x4EEC;&#x4F7F;&#x7528;&#x6591;&#x9A6C;&#x9C7C;&#xFF0C;&#x5FC3;&#x810F;&#x5F62;&#x6210;&#x7684;&#x8C03;&#x63A7;&#x51FA;&#x73B0;&#x4F53;&#x5185;&#x610F;&#x4E49; Tbx5/Pdlim7 &#x86CB;&#x767D;&#x8D28;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x5FC5;&#x4E0D;&#x53EF;&#x5C11;&#x7684;&#x4F5C;&#x7528;&#x3002;Pdlim7 &#x649E;&#x5BFC;&#x81F4;&#x975E;&#x73AF;&#x7684;&#x5FC3;&#x810F;&#xFF0C;&#x60CA;&#x4EBA;&#x5730;&#x8BA9;&#x4EBA;&#x60F3;&#x8D77; tbx5 &#x5FC3;&#x5F26;&#x7A81;&#x53D8;&#x8868;&#x578B;&#x3002;&#x7136;&#x800C;&#xFF0C;&#x867D;&#x7136; Pdlim7 &#x548C; Tbx5 &#x98CE;&#x6F6E;&#x4EA7;&#x751F;&#x7C7B;&#x4F3C;&#x5F02;&#x5E38;&#x5FC3;&#x810F;&#x5F62;&#x6001;&#xFF0C;&#x5206;&#x5B50;&#x548C;&#x7EC4;&#x7EC7;&#x5B66;&#x5206;&#x6790;&#x53D1;&#x73B0;&#x4E86; Pdlim7 &#x548C; Tbx5 &#x5FC3;&#x810F;&#x8868;&#x578B;&#x662F;&#x76F8;&#x53CD;&#x7684;&#x6548;&#x679C;&#xFF0C;&#x5BF9;&#x9600;&#x95E8;&#x7684;&#x5F00;&#x53D1;&#x3002;Pdlim7 &#x529F;&#x80FD;&#x7684;&#x4E27;&#x5931;&#x4F1A;&#x5BFC;&#x81F4;&#x65E0;&#x9600;&#x7EC4;&#x7EC7;&#x540C;&#x65F6;&#x7F3A;&#x4E4F; Tbx5 &#x7ED3;&#x679C;&#x589E;&#x52A0;&#x7684;&#x74E3;&#x819C;&#x7EC4;&#x7EC7;&#x4E2D;&#x53D1;&#x5C55;&#x3002;&#x8FD9;&#x4E9B;&#x5BF9;&#x7ACB;&#x7684;&#x7F3A;&#x9677;&#x662F;&#x660E;&#x663E;&#x9600;&#x95E8;&#x5F62;&#x6210;&#x4E4B;&#x524D;&#xFF0C;&#x4E0D;&#x540C;&#x57FA;&#x56E0;&#x98CE;&#x6F6E;&#x671F;&#x95F4;&#x7684;&#x623F;&#x5BA4; (AV) &#x8FB9;&#x754C;&#x89C4;&#x8303;&#x7684;&#x7ED3;&#x679C;&#x3002;&#x6211;&#x4EEC;&#x5C55;&#x793A; Pdlim7/Tbx5 &#x4EA4;&#x4E92;&#x5F71;&#x54CD; Tbx5 &#x76EE;&#x6807;&#x57FA;&#x56E0;&#x5B9E;&#x65BD;&#x548C;&#x5728; AV &#x754C;&#x4E2D;&#xFF0C;tbx2b &#x7684;&#x8868;&#x8FBE;&#x548C;&#x5176;&#x57DF;&#x7684; misexpression &#x76F4;&#x63A5;&#x5173;&#x8054;&#x786E;&#x5B9A;&#x7684;&#x9600;&#x7F3A;&#x635F;&#x3002;&#x8FD9;&#x4E9B;&#x7814;&#x7A76;&#x8868;&#x660E;&#x63A7;&#x5236; Tbx5 &#x6D3B;&#x52A8;&#x7684;&#x6B63;&#x786E;&#x7684;&#x5E73;&#x8861;&#x662F;&#x5173;&#x952E;&#x7684; AV &#x8FB9;&#x754C;&#x548C;&#x9600;&#x95E8;&#x5F62;&#x6210;&#x89C4;&#x8303;&#x3002;

Pdlim7 (LMP4) &#x89C4;&#x4F8B; Tbx5 &#x7684;&#x6307;&#x5B9A;&#x6591;&#x9A6C;&#x9C7C;&#x5FC3;&#x810F;&#x623F;&#x5BA4;&#x8FB9;&#x754C;&#x548C;&#x9600;&#x95E8;&#x5F62;&#x6210;&#x3002;

Tbx5 is involved in congenital heart disease, however, the mechanisms leading to organ malformation are greatly unknown. We hypothesized a model by which the Tbx5 binding protein Pdlim7 controls nuclear/cytoplasmic shuttling and function of the transcription factor. Using the zebrafish, we present in vivo significance for an essential role of Tbx5/Pdlim7 protein interaction in the regulation of cardiac formation. Knock-down of Pdlim7 results in a non-looped heart, strikingly reminiscent of the tbx5 heartstrings mutant phenotype. However, while misregulation of Pdlim7 and Tbx5 produce similar aberrant cardiac morphology, molecular and histological analysis uncovered that the Pdlim7 and Tbx5 cardiac phenotypes are due to opposite effects on valve development. Loss of Pdlim7 function causes no valve tissue to develop while lack of Tbx5 results in increased valve tissue. These opposing defects are evident before valve formation and are the result of distinct gene misregulation during specification of the atrio-ventricular (AV) boundary. We show that Pdlim7/Tbx5 interactions affect the expression of Tbx5 target genes nppa and tbx2b at the AV boundary, and their domains of misexpression directly correlate with the identified valve defects. These studies demonstrate that controlling the correct balance of Tbx5 activity is crucial for the specification of the AV boundary and valve formation.

Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart atrio-ventricular boundary and valve formation.

Tbx5 est impliqu&#xE9;e dans la maladie cardiaque cong&#xE9;nitale, cependant, les m&#xE9;canismes conduisant &#xE0; une malformation d&#x26;#39;organes sont grandement inconnues. Nous &#xE9;mettons l&#x26;#39;hypoth&#xE8;se d&#x26;#39;un mod&#xE8;le par lequel la prot&#xE9;ine de liaison Tbx5 Pdlim7 contr&#xF4;le nucl&#xE9;aire / cytoplasmique navette et la fonction du facteur de transcription. En utilisant le poisson z&#xE8;bre, nous pr&#xE9;sentons dans la signification in vivo pour un r&#xF4;le essentiel de Tbx5/Pdlim7 interaction prot&#xE9;ine dans la r&#xE9;gulation de la formation cardiaque. Knock-down de Pdlim7 r&#xE9;sultats dans un c&#x153;ur non-boucle, frappante rappelle le ph&#xE9;notype mutant TBX5 corde sensible. Cependant, alors que d&#xE9;r&#xE8;glement de Pdlim7 et Tbx5 produire m&#xEA;me morphologie aberrante cardiaque, mol&#xE9;culaire et l&#x26;#39;analyse histologique d&#xE9;couvert que les Pdlim7 et Tbx5 ph&#xE9;notypes cardiaques sont dus &#xE0; des effets oppos&#xE9;s sur le d&#xE9;veloppement de soupape. Perte de Pdlim7 fonction ne provoque aucune tissu valvulaire &#xE0; d&#xE9;velopper manque tout de TBX5 r&#xE9;sultats dans le tissu valvulaire accrue. Ces d&#xE9;fauts oppos&#xE9;s sont &#xE9;vidents avant la formation de soupape et sont le r&#xE9;sultat d&#x26;#39;un d&#xE9;r&#xE8;glement du g&#xE8;ne distincte au cours de sp&#xE9;cification de la conduction auriculo-ventriculaire (AV) limite. Nous montrons que Pdlim7/Tbx5 interactions affectent l&#x26;#39;expression des g&#xE8;nes cibles Tbx5 &#xC9;NPP et tbx2b &#xE0; la limite AV, et leurs domaines de d&#xE9;r&#xE9;gulation directement en corr&#xE9;lation avec les d&#xE9;fauts de valve identifi&#xE9;s. Ces &#xE9;tudes d&#xE9;montrent que le contr&#xF4;le de l&#x26;#39;&#xE9;quilibre correct de Tbx5 activit&#xE9; est cruciale pour la sp&#xE9;cification de la fronti&#xE8;re AV et la formation de la vanne.

Pdlim7 (LMP4) Le r&#xE8;glement de Tbx5 Sp&#xE9;cifie c&#x153;ur du poisson z&#xE8;bre auriculo-ventriculaire fronti&#xE8;re et de la Formation Valve

Angeborene Herzfehler Tbx5 beteiligt ist, jedoch die Mechanismen zur Organ-Fehlbildungen sind sehr unbekannt. Wir die Hypothese eines Modells, das nukleare/zytoplasmatischen pendelt und Funktion des Transkriptionsfaktors Tbx5 verbindliches Protein Pdlim7 steuert. Mithilfe der Zebrafisch, pr&auml;sentieren wir in-vivo Bedeutung f&uuml;r eine wesentliche Rolle des Tbx5/Pdlim7-Protein-Interaktion bei der Regulierung der kardialen Bildung. Knock-Down der Pdlim7 f&uuml;hrt ein nicht geloopt Herz, auffallend erinnert an die tbx5 Heartstrings mutant Ph&auml;notyp. Jedoch Misregulation Pdlim7 und Tbx5 produzieren &auml;hnliche aberrante kardiale Morphologie, Molekulare und histologische Analyse aufgedeckt, dass die Pdlim7 und Tbx5 kardialen Ph&auml;notypen durch entgegengesetzte Wirkungen auf die Ventil-Entwicklung sind. Pdlim7 Funktionsverlust bewirkt, dass kein Ventil-Gewebe, w&auml;hrend mangelnde Tbx5 f&uuml;hrt zu erh&ouml;hten Ventil Gewebe zu entwickeln. Diese gegens&auml;tzlichen M&auml;ngel sind vor Ventil Entstehung und resultieren aus unterschiedlichen gen Misregulation w&auml;hrend der Spezifikation der Atrio-ventrikul&auml;re (AV)-Grenze. Wir zeigen, dass Pdlim7/Tbx5 Interaktionen den Ausdruck Tbx5 deiner Gene Nppa und tbx2b an der AV-Grenze und ihre Domains von Misexpression direkt mit der identifizierten Ventil-defekten korrelieren. Diese Studien zeigen, dass die richtige Balance von Tbx5 Aktivit&auml;t Steuern entscheidend f&uuml;r die Spezifikation der AV-Grenze und Ventil-Formation ist.

Pdlim7 (LMP4) Regulierung der Tbx5 gibt Zebrafisch-Herz Atrio-ventrikul&auml;re Grenze und Ventil-Bildung.

Tbx5 &egrave; coinvolto nella malattia di cuore congenita, tuttavia, i meccanismi che portano a malformazione organo sono grandemente sconosciuti. Abbiamo ipotizzato un modello da cui la proteina Tbx5 Pdlim7 controlla la spola nucleare/citoplasmatica e la funzione del fattore di trascrizione. Utilizzando il Danio zebrato, presentiamo in vivo significato per un ruolo essenziale di interazione della proteina Tbx5/Pdlim7 nella regolazione della formazione cardiaco. Knock-down di Pdlim7 risultati in un cuore non cappio, sorprendentemente ricordano del fenotipo mutante tbx5 commuovere. Tuttavia, mentre i misregolazione di Pdlim7 e Tbx5 producono simile aberranti morfologia cardiaca, analisi istologica e molecolare ha scoperto che i Pdlim7 e Tbx5 fenotipi cardiaci sono dovuti a effetti opposti sullo sviluppo della valvola. Perdita della funzione Pdlim7 non cause tessuto valvola a sviluppare durante la mancanza di risultati Tbx5 in tessuto aumentato valvola. Questi difetti opposti sono evidenti prima della formazione della valvola e sono il risultato di misregolazione distinti gene durante la specificazione del limite atrio-ventricolare (AV). Mostriamo che Pdlim7/Tbx5 interazioni possono influenzare l&#39;espressione Tbx5 bersaglio geni nppa e tbx2b al confine AV, e i domini di misexpression correlano direttamente con i difetti individuati valvola. Questi studi dimostrano che controlla il corretto equilibrio di Tbx5 attivit&agrave; &egrave; cruciale per la specifica della formazione di confine e valvola AV.

Pdlim7 (LMP4) regolamento di Tbx5 specifica Danio rerio atrio-ventricolare contorno e valvola formazione del cuore.

TBX5&#x306F;&#x3001;&#x5148;&#x5929;&#x6027;&#x5FC3;&#x75BE;&#x60A3;&#x306B;&#x95A2;&#x4E0E;&#x3057;&#x3066;&#x3044;&#x308B;&#x304C;&#x3001;&#x81D3;&#x5668;&#x306E;&#x5947;&#x5F62;&#x3092;&#x5F15;&#x304D;&#x8D77;&#x3053;&#x3059;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x306F;&#x975E;&#x5E38;&#x306B;&#x4E0D;&#x660E;&#x3067;&#x3042;&#x308B;&#x3002;&#x6211;&#x3005;&#x306F;TBX5&#x7D50;&#x5408;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;Pdlim7&#x306F;&#x3001;&#x6838;/&#x7D30;&#x80DE;&#x8CEA;&#x30B7;&#x30E3;&#x30C8;&#x30EB;&#x3068;&#x8EE2;&#x5199;&#x56E0;&#x5B50;&#x306E;&#x6A5F;&#x80FD;&#x3092;&#x5236;&#x5FA1;&#x3059;&#x308B;&#x3053;&#x3068;&#x306B;&#x3088;&#x3063;&#x3066;&#x3001;&#x30E2;&#x30C7;&#x30EB;&#x3092;&#x4EEE;&#x5B9A;&#x3057;&#x305F;&#x3002;&#x30BC;&#x30D6;&#x30E9;&#x30D5;&#x30A3;&#x30C3;&#x30B7;&#x30E5;&#x3092;&#x7528;&#x3044;&#x3066;&#x3001;&#x6211;&#x3005;&#x306F;&#x3001;&#x5FC3;&#x81D3;&#x306E;&#x5F62;&#x6210;&#x306E;&#x8ABF;&#x7BC0;&#x306B;Tbx5/Pdlim7&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x306E;&#x91CD;&#x8981;&#x306A;&#x5F79;&#x5272;&#x306E;&#x305F;&#x3081;&#x306E;in vivo&#x3067;&#x6709;&#x610F;&#x306B;&#x5B58;&#x5728;&#x3059;&#x308B;&#x3002;&#x30CE;&#x30C3;&#x30AF;&#x30C0;&#x30A6;&#x30F3;TBX5&#x7434;&#x7DDA;&#x5909;&#x7570;&#x4F53;&#x306E;&#x8868;&#x73FE;&#x578B;&#x306E;&#x8457;&#x3057;&#x304F;&#x5F77;&#x5F7F;&#x3068;&#x3055;&#x305B;&#x308B;&#x975E;&#x30EB;&#x30FC;&#x30D7;&#x4E2D;&#x5FC3;&#x90E8;&#x306E;Pdlim7&#x7D50;&#x679C;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;Pdlim7&#x3068;TBX5&#x306E;&#x5236;&#x5FA1;&#x30DF;&#x30B9;&#x306F;&#x3001;&#x540C;&#x69D8;&#x306E;&#x7570;&#x5E38;&#x306A;&#x5FC3;&#x81D3;&#x306E;&#x5F62;&#x614B;&#x3001;&#x5206;&#x5B50;Pdlim7&#x3068;TBX5&#x5FC3;&#x81D3;&#x306E;&#x8868;&#x73FE;&#x578B;&#x306F;&#x3001;&#x30D0;&#x30EB;&#x30D6;&#x306E;&#x958B;&#x767A;&#x306B;&#x53CD;&#x5BFE;&#x306E;&#x52B9;&#x679C;&#x306B;&#x3088;&#x308B;&#x3082;&#x306E;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x660E;&#x3089;&#x304B;&#x306B;&#x7D44;&#x7E54;&#x5B66;&#x7684;&#x5206;&#x6790;&#x3092;&#x751F;&#x6210;&#x3057;&#x305F;&#x3002; Pdlim7&#x6A5F;&#x80FD;&#x306E;&#x640D;&#x5931;&#x304C;&#x5897;&#x52A0;&#x3057;&#x305F;&#x5F01;&#x7D44;&#x7E54;&#x306B;&#x304A;&#x3051;&#x308B;TBX5&#x7D50;&#x679C;&#x306E;&#x4E2D;&#x306B;&#x6B20;&#x5982;&#x3092;&#x958B;&#x767A;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x306F;&#x5F01;&#x7D44;&#x7E54;&#x3092;&#x5F15;&#x304D;&#x8D77;&#x3053;&#x3057;&#x307E;&#x305B;&#x3093;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x76F8;&#x53CD;&#x3059;&#x308B;&#x6B20;&#x9665;&#x306F;&#x3001;&#x5F01;&#x5F62;&#x6210;&#x306E;&#x524D;&#x306B;&#x660E;&#x3089;&#x304B;&#x3067;&#x3042;&#x308A;&#x3001;&#x623F;&#x5BA4;&#xFF08;AV&#xFF09;&#x306E;&#x5883;&#x754C;&#x306E;&#x4ED5;&#x69D8;&#x306E;&#x9593;&#x306B;&#x5225;&#x500B;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x5236;&#x5FA1;&#x30DF;&#x30B9;&#x306E;&#x7D50;&#x679C;&#x3067;&#x3042;&#x308B;&#x3002;&#x6211;&#x3005;&#x306F;Pdlim7/Tbx5&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x304C;NPPA&#x3068;tbx2b AV&#x5883;&#x754C;&#x3067;&#x3001;&#x3068;&#x5F37;&#x5236;&#x767A;&#x73FE;&#x306E;&#x305D;&#x308C;&#x3089;&#x306E;&#x30C9;&#x30E1;&#x30A4;&#x30F3;&#x304C;&#x76F4;&#x63A5;&#x8B58;&#x5225;&#x3055;&#x308C;&#x308B;&#x30D0;&#x30EB;&#x30D6;&#x306E;&#x6B20;&#x9665;&#x3068;&#x306E;&#x76F8;&#x95A2;TBX5&#x6A19;&#x7684;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x767A;&#x73FE;&#x306B;&#x5F71;&#x97FF;&#x3092;&#x200B;&#x200B;&#x53CA;&#x307C;&#x3059;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x7814;&#x7A76;&#x306F;&#x3001;TBX5&#x6D3B;&#x52D5;&#x306E;&#x6B63;&#x3057;&#x3044;&#x30D0;&#x30E9;&#x30F3;&#x30B9;&#x3092;&#x5236;&#x5FA1;&#x3059;&#x308B;AV&#x5883;&#x754C;&#x3068;&#x5F01;&#x5F62;&#x6210;&#x306E;&#x4ED5;&#x69D8;&#x306E;&#x305F;&#x3081;&#x306B;&#x91CD;&#x8981;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

TBX5&#x306E;Pdlim7&#xFF08;LMP4&#xFF09;&#x898F;&#x5236;&#x306F;&#x3001;&#x30BC;&#x30D6;&#x30E9;&#x30D5;&#x30A3;&#x30C3;&#x30B7;&#x30E5;&#x306E;&#x5FC3;&#x81D3;&#x623F;&#x5BA4;&#x5883;&#x754C;&#x3068;&#x5F01;&#x5F62;&#x6210;&#x3092;&#x6307;&#x5B9A;&#x3057;&#x307E;&#x3059;&#x3002;

Tbx5 est&#xE1; implicado en la enfermedad cardiaca cong&#xE9;nita, sin embargo, los mecanismos que conducen a la malformaci&#xF3;n de &#xF3;rganos son en gran medida desconocido. La hip&#xF3;tesis de un modelo por el cual la prote&#xED;na de uni&#xF3;n Tbx5 Pdlim7 controla n&#xFA;cleo / citoplasma yendo y viniendo y la funci&#xF3;n del factor de transcripci&#xF3;n. Usando el pez cebra, que presentamos en vivo importancia de un papel esencial de la interacci&#xF3;n prote&#xED;na Tbx5/Pdlim7 en la regulaci&#xF3;n de la formaci&#xF3;n cardiaca. Knock-down de Pdlim7 resultados en un coraz&#xF3;n no en bucle, sorprendentemente reminiscente del fenotipo mutante Tbx5 fibras del coraz&#xF3;n. Sin embargo, mientras que una regulaci&#xF3;n deficiente de Pdlim7 y Tbx5 producen similares aberrante morfolog&#xED;a card&#xED;aca, molecular y el an&#xE1;lisis histol&#xF3;gico revel&#xF3; que los Pdlim7 y Tbx5 fenotipos card&#xED;acos se deben a efectos opuestos sobre el desarrollo de la v&#xE1;lvula. La p&#xE9;rdida de la funci&#xF3;n Pdlim7 no causa ning&#xFA;n tejido de la v&#xE1;lvula para el desarrollo, mientras que la falta de Tbx5 resultados en el tejido de la v&#xE1;lvula mayor. Estos defectos se oponen son evidentes antes de la formaci&#xF3;n de la v&#xE1;lvula y son el resultado de una regulaci&#xF3;n defectuosa del gen distinta durante la especificaci&#xF3;n de la aur&#xED;culo-ventricular (AV) l&#xED;mite. Se demuestra que Pdlim7/Tbx5 interacciones afectan la expresi&#xF3;n de los genes diana Tbx5 NPPA y tbx2b en el l&#xED;mite de AV, y sus dominios de misexpression se correlacionan directamente con los defectos en las v&#xE1;lvulas identificadas. Estos estudios demuestran que el control del equilibrio correcto de Tbx5 actividad es crucial para la especificaci&#xF3;n de la frontera AV y la formaci&#xF3;n de la v&#xE1;lvula.

Pdlim7 (LMP4) El Reglamento de Tbx5 Especifica coraz&#xF3;n del pez cebra atrioventricular de L&#xED;mites y formaci&#xF3;n de la v&#xE1;lvula

Recent work on the PDZ-LIM protein family has revealed that it has important activities at the cellular level, mediating signals between the nucleus and the cytoskeleton, with significant impact on organ development. We review and integrate current knowledge about the PDZ-LIM protein family and propose a new functional role, sequestering nuclear factors in the cytoplasm. Characterized by their PDZ and LIM domains, the PDZ-LIM family is comprised of evolutionarily conserved proteins found throughout the animal kingdom, from worms to humans. Combining two functional domains in one protein, PDZ-LIM proteins have wide-ranging and multi-compartmental cell functions during development and homeostasis. In contrast, misregulation can lead to cancer formation and progression. New emerging roles include interactions with integrins, T-box transcription factors, and receptor tyrosine kinases. Facilitating the assembly of protein complexes, PDZ-LIM proteins can act as signal modulators, influence actin dynamics, regulate cell architecture, and control gene transcription.

Nucleocytoplasmic functions of the PDZ-LIM protein family: new insights into organ development.

Vertebrate limb development involves a reciprocal feedback loop between limb mesenchyme and the overlying apical ectodermal ridge (AER). Several gene pathways participate in this feedback loop, including Fgf signaling. In the forelimb lateral plate mesenchyme, Tbx5 activates Fgf10 expression, which in turn initiates and maintains the mesenchyme/AER Fgf signaling loop. Recent findings have revealed that Tbx5 transcriptional activity is regulated by dynamic nucleocytoplasmic shuttling and interaction with Pdlim7, a PDZ-LIM protein family member, along actin filaments. This Tbx5 regulation is critical in heart formation, but the coexpression of both proteins in other developing tissues suggests a broader functional role.

Pdlim7 is required for maintenance of the mesenchymal/epidermal Fgf signaling feedback loop during zebrafish pectoral fin development.

Acute kidney injury (AKI) is a common and significant medical problem. Despite the kidney's remarkable regenerative capacity, the mortality rate for the AKI patients is high. Thus, there remains a need to better understand the cellular mechanisms of nephron repair in order to develop new strategies that would enhance the intrinsic ability of kidney tissue to regenerate. Here, using a novel, laser ablation-based, zebrafish model of AKI, we show that collective migration of kidney epithelial cells is a primary early response to acute injury. We also show that cell proliferation is a late response of regenerating kidney epithelia that follows cell migration during kidney repair. We propose a computational model that predicts this temporal relationship and suggests that cell stretch is a mechanical link between migration and proliferation, and present experimental evidence in support of this hypothesis. Overall, this study advances our understanding of kidney repair mechanisms by highlighting a primary role for collective cell migration, laying a foundation for new approaches to treatment of AKI.

Collective epithelial migration drives kidney repair after acute injury.

Acute kidney injury, often caused by an ischemic insult, is associated with significant short-term morbidity and mortality, and increased risk of chronic kidney disease. The factors affecting the renal response to injury following ischemia and reperfusion remain to be clarified. We found that the Stem cell antigen-1 (Sca-1), commonly used as a stem cell marker, is heavily expressed in renal tubules of the adult mouse kidney. We evaluated its potential role in the kidney using Sca-1 knockout mice submitted to acute ischemia reperfusion injury (IRI), as well as cultured renal proximal tubular cells in which Sca-1 was stably silenced with shRNA. IRI induced more severe injury in Sca-1 null kidneys, as assessed by increased expression of Kim-1 and Ngal, rise in serum creatinine, abnormal pathology, and increased apoptosis of tubular epithelium, and persistent significant renal injury at day 7 post IRI, when recovery of renal function in control animals was nearly complete. Serum creatinine, Kim-1 and Ngal were slightly but significantly elevated even in uninjured Sca-1-/- kidneys. Sca-1 constitutively bound both TGFβ receptors I and II in cultured normal proximal tubular epithelial cells. Its genetic loss or silencing lead to constitutive TGFβ receptor-mediated activation of canonical Smad signaling even in the absence of ligand and to KIM-1 expression in the silenced cells. These studies demonstrate that by normally repressing TGFβ-mediated canonical Smad signaling, Sca-1 plays an important in renal epithelial cell homeostasis and in recovery of renal function following ischemic acute kidney injury.

Negative Regulation of TGFβ Signaling by Stem Cell Antigen-1 Protects against Ischemic Acute Kidney Injury.

New nephron formation (nephrogenesis) ceases in mammals around birth and is completely absent in adults. In contrast, postembryonic nephrogenesis is well documented in the mesonephric kidneys of fishes and amphibians. The transient mesonephros in reptiles (including birds) and mammals is replaced by the metanephros during embryogenesis. Thus, one may speculate that postembryonic nephrogenesis is restricted to the mesonephric kidney. Previous reports have suggested the metanephros of non-avian reptiles (hereafter reptiles) may continually form nephrons throughout life. We investigated the presence of adult nephrogenesis in reptiles by examining adult kidneys from several species including Trachemys scripta, Chrysemys picta, Boa constrictor, Tupinambis tegu, Anolis carolinensis, and Alligator mississipiensis among others. We found that all major reptilian groups (Testudines, Crocodylia, and Squamates) showed the presence of adult nephrogenesis. The total amount of nephrogenesis varied greatly between species with turtles displaying the highest density of nephrogenesis. In contrast, we were unable to detect adult nephrogenesis in monotremes, and in the iguanid A. carolinensis. Nephron progenitor cells express the transcription factor Six2, which in mammals, becomes downregulated as the progenitor cell population is exhausted and nephrogenesis ends. Using the alligator as a model, we were able to detect Six2-positive cap mesenchyme cells in the adult kidney, which spatially correlated with areas of nephrogenesis. These results suggest that the metanephric kidney of reptiles has maintained the ability to continually grow new nephrons during postembryonic life, a process lost early in mammalian evolution, likely due to the persistence of a Six2-expressing progenitor cell population.

Postembryonic Nephrogenesis and Persistence of Six2-Expressing Nephron Progenitor Cells in the Reptilian Kidney.

Mustn1 is a small nuclear protein that is involved in the development and regeneration of the musculoskeletal system. Previous work established a role for Mustn1 in myogenic and chondrogenic differentiation. In addition, recent evidence suggests a potential role for Mustn1 in cilia function in zebrafish. A detailed study of Mustn1 expression has yet to be conducted in zebrafish. As such, we report herein the cloning of the zebrafish Mustn1 orthologs, mustn1a and mustn1b, and their expression during zebrafish embryonic and larval development. Results indicate a 44% nucleotide identity between the two paralogs. Phylogenetic analysis further confirmed that the Mustn1a and 1b predicted proteins were highly related to other vertebrate members of the Mustn1 protein family. Whole mount in situ hybridization revealed expression of both mustn1a and 1b at the 7-somite stage through 72hpf in structures such as Kupffer's vesicle, segmental mesoderm, head structures, and otic vesicle. Additionally, in 5day old larva, mustn1a and 1b expression is detected in the neurocranium, otic capsule, and the gut. Although both were expressed in the neurocranium, mustn1a was localized in the hypophyseal fenestra whereas mustn1b was found near the posterior basicapsular commissure. mustn1b also displayed expression in the ceratohyal and ceratobranchial elements of the pharyngeal skeleton. These expression patterns were verified temporally by q-PCR analysis. Taken together, we conclude that Mustn1 expression is conserved in vertebrates and that the variations in expression of the two zebrafish paralogs suggest different modes of molecular regulation.

Troy Camarata

Department of Basic Sciences

NYITCOM-A-State

Precise Cellular Ablation Approach for Modeling Acute Kidney Injury in Developing Zebrafish

Troy Camarata

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Basic Sciences

NYITCOM-A-State

Precise Cellular Ablation Approach for Modeling Acute Kidney Injury in Developing Zebrafish

Department of Basic Sciences