Novel Roles of GATA4/6 in the Postnatal Heart Identified through Temporally Controlled, Cardiomyocyte-Specific Gene Inactivation by Adeno-Associated Virus Delivery of Cre Recombinase.
Novel Roles of GATA4/6 in the Postnatal Heart Identified through Temporally Controlled, Cardiomyocyte-Specific Gene Inactivation by Adeno-Associated Virus Delivery of Cre Recombinase.
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DOI：
10.1371/journal.pone.0128105
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Pu WT
中科院分区：
文献类型：
--
作者：
Prendiville TW;Guo H;Lin Z;Zhou P;Stevens SM;He A;VanDusen N;Chen J;Zhong L;Wang DZ;Gao G;Pu WT
GATA 4和GATA 6是心脏的核心转录调节因子。出生后，心脏转录因子GATA 4和GATA 6的阶段特异性功能尚未评估。在某种程度上，这是因为目前的Cre-loxP心脏基因失活方法需要耗时和昂贵的Cre表达和“floxed”小鼠品系的育种，通常对基因失活的程度或时间的控制有限。我们研究了GATA 4和GATA 6在出生后心脏中的阶段特异性功能，通过使用腺相关病毒血清型9来控制Cre基因失活的时间和程度。从心脏特异性Tnnt 2启动子表达Cre的重组腺相关病毒9（AAV 9）的全身递送耐受性良好，并且在心肌细胞中选择性且有效地重组floxed靶基因。AAV 9：Tnnt 2-Cre有效灭活Gata 4和Gata 6。新生儿Gata 4/6失活导致严重的、快速致死的收缩性心力衰竭。相反，Gata 4/6失活在成人心脏中仅引起轻度收缩功能障碍，但严重舒张功能障碍。降低AAV 9：Tnnt 2-Cre的剂量产生了其中分散的心肌细胞缺乏Gata 4/6的嵌合体。这种嵌合敲除揭示了Gata 4/6是生理性心肌细胞生长所需的细胞自主性。我们的研究结果定义了GATA 4和GATA 6在新生儿和成人心脏中的新作用。此外，我们的数据表明，基因功能的评估取决于控制基因失活的时间和程度。AAV 9：Tnnt 2-Cre是控制这些参数的强大工具。
GATA4 and GATA6 are central cardiac transcriptional regulators. The postnatal, stage-specific function of the cardiac transcription factors GATA4 and GATA6 have not been evaluated. In part, this is because current Cre-loxP approaches to cardiac gene inactivation require time consuming and costly breeding of Cre-expressing and “floxed” mouse lines, often with limited control of the extent or timing of gene inactivation. We investigated the stage-specific functions of GATA4 and GATA6 in the postnatal heart by using adeno-associated virus serotype 9 to control the timing and extent of gene inactivation by Cre. Systemic delivery of recombinant, adeno-associated virus 9 (AAV9) expressing Cre from the cardiac specific Tnnt2 promoter was well tolerated and selectively and efficiently recombined floxed target genes in cardiomyocytes. AAV9:Tnnt2-Cre efficiently inactivated Gata4 and Gata6. Neonatal Gata4/6 inactivation caused severe, rapidly lethal systolic heart failure. In contrast, Gata4/6 inactivation in adult heart caused only mild systolic dysfunction but severe diastolic dysfunction. Reducing the dose of AAV9:Tnnt2-Cre generated mosaics in which scattered cardiomyocytes lacked Gata4/6. This mosaic knockout revealed that Gata4/6 are required cell autonomously for physiological cardiomyocyte growth. Our results define novel roles of GATA4 and GATA6 in the neonatal and adult heart. Furthermore, our data demonstrate that evaluation of gene function hinges on controlling the timing and extent of gene inactivation. AAV9:Tnnt2-Cre is a powerful tool for controlling these parameters.
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影响因子：
3.7
作者：
van Berlo JH;Aronow BJ;Molkentin JD
通讯作者：
Molkentin JD
DOI：
10.1073/pnas.85.2.339
发表时间：
1988-01-01
影响因子：
11.1
作者：
IZUMO, S;NADALGINARD, B;MAHDAVI, V
通讯作者：
MAHDAVI, V
影响因子：
5.3
作者：
MOLKENTIN, JD;KALVAKOLANU, DV;MARKHAM, BE
通讯作者：
MARKHAM, BE
影响因子：
20.1
作者：
Oka, T;Maillet, M;Molkentin, JD
通讯作者：
Molkentin, JD
影响因子：
20.1
作者：
Sohal, DS;Nghiem, M;Molkentin, JD
通讯作者：
Molkentin, JD