Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart atrio-ventricular boundary and valve formation.
Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart atrio-ventricular boundary and valve formation.
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DOI：
10.1016/j.ydbio.2009.10.039
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发表时间：
2010-01-15
影响因子：
2.7
通讯作者：
Simon, Hans-Georg
中科院分区：
文献类型：
--
作者：
Camarata, Troy;Krcmery, Jennifer;Snyder, Diana;Park, Susan;Topczewski, Jacek;Simon, Hans-Georg
Tbx5参与先天性心脏病，但其导致器官畸形的机制尚不清楚。我们假设了Tbx5结合蛋白Pdlim7控制核/细胞质穿梭和转录因子功能的模型。利用斑马鱼，我们提出了Tbx5/Pdlim7蛋白相互作用在心脏形成调节中的重要作用的体内意义。Pdlim7基因的敲除会导致非环状心脏，这与tbx5心肌突变表型惊人地相似。然而，虽然Pdlim7和Tbx5的错误调控会产生类似的异常心脏形态，但分子和组织学分析发现，Pdlim7和Tbx5的心脏表型是由于对瓣膜发育的相反影响。Pdlim7功能缺失导致瓣膜组织不发育，而Tbx5缺失导致瓣膜组织增加。这些相反的缺陷在瓣膜形成之前是明显的，并且是在房室（AV）边界规范期间明显的基因失调的结果。我们发现Pdlim7/Tbx5相互作用影响Tbx5靶基因nppa和tbx2b在AV边界的表达，它们的错误表达域与鉴定的瓣膜缺陷直接相关。这些研究表明，控制Tbx5活性的正确平衡对于AV边界的规范和瓣膜的形成至关重要。
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.
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影响因子：
3.8
作者：
Gopalan, SM;Flaim, C;McCulloch, AD
通讯作者：
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影响因子：
3.3
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Simon, Hans-Georg
影响因子：
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作者：
DELACRUZ, MV;GIMENEZRIBOTTA, M;CAYRE, R
通讯作者：
CAYRE, R