Transmembrane protein 88: a Wnt regulatory protein that specifies cardiomyocyte development
Transmembrane protein 88: a Wnt regulatory protein that specifies cardiomyocyte development
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DOI：
10.1242/dev.094789
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发表时间：
2013-09-15
期刊：
影响因子：
4.6
通讯作者：
Murry, Charles E.
中科院分区：
文献类型：
--
作者：
Palpant, Nathan J.;Pabon, Lil;Murry, Charles E.
从侧板中胚层到心肌细胞的特化的细胞命运转变的遗传调节需要抑制Wnt/β-连环蛋白信号传导，但其机制尚不清楚。通过分析人胚胎干细胞定向分化过程中的基因表达和染色质动力学，我们确定了Wnt/β-连环蛋白信号转导抑制因子跨膜蛋白88（TMEM 88）作为心血管祖细胞（CVP）特化的潜在调节因子。在从中胚层到CVP的过渡期间，TMEM 88具有介导细胞命运决定的基因的染色质特征，并且其表达在体外和体内的关键心脏转录因子之前高度上调。在早期斑马鱼胚胎中，tmem 88 a广泛表达于侧板中胚层，包括双侧心脏区域。在hESC心脏分化过程中靶向TMEM 88的短发夹RNA增加了Wnt/β-连环蛋白信号传导，证实了其作为该途径抑制剂的作用。TMEM 88敲低对NKX2.5或GATA 4表达没有影响，但在CVP发育期间最高度诱导的80%的基因表达降低，表明采用新的细胞命运。为了支持这一点，后期细胞分化的分析显示TMEM 88敲低抑制心肌细胞分化并促进内皮细胞分化。总之，TMEM 88对于心脏发育至关重要，并且在前心中胚层中的加塔因子的下游起作用，以通过抑制Wnt/β-连环蛋白信号传导来指定心肌细胞发育的谱系定型。
Genetic regulation of the cell fate transition from lateral plate mesoderm to the specification of cardiomyocytes requires suppression of Wnt/beta-catenin signaling, but the mechanism for this is not well understood. By analyzing gene expression and chromatin dynamics during directed differentiation of human embryonic stem cells (hESCs), we identified a suppressor of Wnt/beta-catenin signaling, transmembrane protein 88 (TMEM88), as a potential regulator of cardiovascular progenitor cell (CVP) specification. During the transition from mesoderm to the CVP, TMEM88 has a chromatin signature of genes that mediate cell fate decisions, and its expression is highly upregulated in advance of key cardiac transcription factors in vitro and in vivo. In early zebrafish embryos, tmem88a is expressed broadly in the lateral plate mesoderm, including the bilateral heart fields. Short hairpin RNA targeting of TMEM88 during hESC cardiac differentiation increases Wnt/beta-catenin signaling, confirming its role as a suppressor of this pathway. TMEM88 knockdown has no effect on NKX2.5 or GATA4 expression, but 80% of genes most highly induced during CVP development have reduced expression, suggesting adoption of a new cell fate. In support of this, analysis of later stage cell differentiation showed that TMEM88 knockdown inhibits cardiomyocyte differentiation and promotes endothelial differentiation. Taken together, TMEM88 is crucial for heart development and acts downstream of GATA factors in the pre-cardiac mesoderm to specify lineage commitment of cardiomyocyte development through inhibition of Wnt/beta-catenin signaling.