GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFβ signaling.
GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFβ signaling.
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GLUT10 是心血管系统和脊索发育所必需的，并将线粒体功能与 TGFβ 信号连接起来。
DOI：
10.1093/hmg/ddr555
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发表时间：
2012
影响因子：
3.5
通讯作者：
Urban,Zsolt
中科院分区：
文献类型：
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作者：
Willaert,Andy;Khatri,Sandeep;Callewaert,BertL;Coucke,PaulJ;Crosby,SethD;Lee,JosephGH;Davis,ElaineC;Shiva,Sruti;Tsang,Michael;DePaepe,Anne;Urban,Zsolt
生长因子信号传导导致细胞中的显著表型变化，这需要细胞代谢的相应改变。SLC 2A 10/GLUT 10（易化葡萄糖转运蛋白家族成员）突变与动脉迂曲综合征（ATS）患者转化生长因子-β（TGFβ）信号转导改变相关。这项工作的目的是测试SLC 2A 10/GLUT 10是否可以作为TGFβ相关的转录调控和发育过程中的代谢之间的联系。在斑马鱼胚胎中，使用反义吗啉代寡核苷酸注射敲低slc 2a 10导致脊索波浪形和心血管异常，心率和血流量降低，这与不完整和不规则的血管图案相结合。这通过用TGFβ受体的小分子抑制剂（tgfbr 1/alk 5）处理来表型模拟。阵列杂交显示，由两种处理引起的转录组水平的变化高度相关，揭示了减少tgfbr 1信号是早期斑马鱼发育中ATS的关键特征。有趣的是，大部分基因在线粒体功能中起主要作用，这些基因在tgfbr 10基因耗尽后特异性失调，而不是通过tgfbr 1抑制。与这些结果一致，slc 2a 10吗啡变体显示呼吸降低和TGFβ报告基因活性降低。最后，共同注射靶向slc 2a 10和smad 7（一种TGFβ抑制剂）的反义吗啉代导致smad 7吗啡样表型的部分拯救，从而抑制了smads下游的scl 2a 10/scl 10功能。总之，通过促进线粒体呼吸和TGFβ信号传导，β 10对心血管发育至关重要。
Growth factor signaling results in dramatic phenotypic changes in cells, which require commensurate alterations in cellular metabolism. Mutations inSLC2A10/GLUT10, a member of the facilitative glucose transporter family, are associated with altered transforming growth factor-β (TGFβ) signaling in patients with arterial tortuosity syndrome (ATS). The objective of this work was to test whetherSLC2A10/GLUT10 can serve as a link between TGFβ-related transcriptional regulation and metabolism during development. In zebrafish embryos, knockdown ofslc2a10using antisense morpholino oligonucleotide injection caused a wavy notochord and cardiovascular abnormalities with a reduced heart rate and blood flow, which was coupled with an incomplete and irregular vascular patterning. This was phenocopied by treatment with a small-molecule inhibitor of TGFβ receptor (tgfbr1/alk5). Array hybridization showed that the changes at the transcriptome level caused by the two treatments were highly correlated, revealing that a reduced tgfbr1 signaling is a key feature of ATS in early zebrafish development. Interestingly, a large proportion of the genes, which were specifically dysregulated after glut10 depletion gene and not by tgfbr1 inhibition, play a major role in mitochondrial function. Consistent with these results,slc2a10morphants showed decreased respiration and reduced TGFβ reporter gene activity. Finally, co-injection of antisense morpholinos targetingslc2a10andsmad7(a TGFβ inhibitor) resulted in a partial rescue ofsmad7morphant phenotypes, suggestingscl2a10/glut10 functions downstream of smads. Taken together, glut10 is essential for cardiovascular development by facilitating both mitochondrial respiration and TGFβ signaling.