Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies.
Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies.
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DOI：
10.1371/journal.pone.0087662
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Christou-Savina S
中科院分区：
文献类型：
--
作者：
Osborn DP;Roccasecca RM;McMurray F;Hernandez-Hernandez V;Mukherjee S;Barroso I;Stemple D;Cox R;Beales PL;Christou-Savina S
人类脂肪量和肥胖相关基因（FTO）中常见的内含子变异被发现与肥胖风险增加有关。FTO的过度表达与食物摄入增加和肥胖相关，而功能丧失导致致死性和严重的发育缺陷。尽管围绕FTO在能量代谢中的作用进行了激烈的科学讨论，但FTO在发育过程中的功能仍然不确定。在这里，我们表明，Fto的损失导致发育缺陷，如生长迟缓，颅面畸形和异常的神经嵴细胞迁移在斑马鱼。我们发现，在体内（斑马鱼）和体外（Fto−/− MEFs和HEK 293 T），重要的发育途径Wnt在没有FTO的情况下受到损害。经典Wnt信号转导通过废除β-连环蛋白易位到细胞核而下调，而非经典Wnt/Ca 2+途径通过其关键信号介质CaMK II和PKCδ激活。此外，我们证明，Fto的损失导致短，缺席或混乱的纤毛导致原位倒置，肾囊肿，神经嵴细胞缺陷和小头症的斑马鱼。相应地，Fto敲除小鼠显示异常的组织特异性纤毛。这些数据将FTO鉴定为Wnt途径的经典分支和非经典分支之间平衡激活的蛋白质调节剂。此外，我们提出的第一个证据表明，FTO在发展和纤毛的形成/功能中发挥作用。
Common intronic variants in the Human fat mass and obesity-associated gene (FTO) are found to be associated with an increased risk of obesity. Overexpression of FTO correlates with increased food intake and obesity, whilst loss-of-function results in lethality and severe developmental defects. Despite intense scientific discussions around the role of FTO in energy metabolism, the function of FTO during development remains undefined. Here, we show that loss of Fto leads to developmental defects such as growth retardation, craniofacial dysmorphism and aberrant neural crest cells migration in Zebrafish. We find that the important developmental pathway, Wnt, is compromised in the absence of FTO, both in vivo (zebrafish) and in vitro (Fto−/− MEFs and HEK293T). Canonical Wnt signalling is down regulated by abrogated β-Catenin translocation to the nucleus whilst non-canonical Wnt/Ca2+ pathway is activated via its key signal mediators CaMKII and PKCδ. Moreover, we demonstrate that loss of Fto results in short, absent or disorganised cilia leading to situs inversus, renal cystogenesis, neural crest cell defects and microcephaly in Zebrafish. Congruently, Fto knockout mice display aberrant tissue specific cilia. These data identify FTO as a protein-regulator of the balanced activation between canonical and non-canonical branches of the Wnt pathway. Furthermore, we present the first evidence that FTO plays a role in development and cilia formation/function.
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影响因子：
30.8
作者：
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影响因子：
10.9
作者：
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通讯作者：
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影响因子：
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10.1016/j.bbrc.2005.03.007
发表时间：
2005-05-06
影响因子：
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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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