ATR promotes cilia signalling: links to developmental impacts.
ATR promotes cilia signalling: links to developmental impacts.
复制标题
ATR促进纤毛信号传导：与发育影响的链接。
DOI：
10.1093/hmg/ddw034
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发表时间：
2016-04-15
影响因子：
3.5
通讯作者：
Philipp M
中科院分区：
文献类型：
--
作者：
Stiff T;Casar Tena T;O'Driscoll M;Jeggo PA;Philipp M
ATR（共济失调毛细血管扩张症和RAD 3相关）的突变导致Seckel综合征（ATR-SS），一种小头原始侏儒症。目前，ATR缺陷的临床表现已归因于其在复制叉停滞/崩溃后的DNA损伤反应信号传导中的典型作用。在这里，我们表明，ATR调节纤毛依赖的信号的方式，可以从其功能在复制过程中解耦。ATR耗尽或患者来源的ATR-SS细胞形成长度略微减少的纤毛，但纤毛依赖性信号传导功能显著受损，包括生长因子和Sonic hedgehog信号传导。为了更好地理解ATR功能丧失对发育的影响，我们还使用斑马鱼作为模型。耗尽Atr的斑马鱼胚胎类似于ATR-SS形态，表现出适度但统计学显著的纤毛长度减少和其他形态特征指示纤毛功能障碍。此外，他们表现出左右不对称的缺陷，包括左撇子的表达不明确，不正确的循环心脏和包括胰腺在内的内脏器官的随机定位，这些特征通常由纤毛功能障碍引起。我们的研究结果揭示了ATR在纤毛信号传导中的新作用，与其在复制过程中的典型功能不同，并加强了纤毛功能与发育之间的联系。
Mutations in ATR (ataxia telangiectasia and RAD3-related) cause Seckel syndrome (ATR-SS), a microcephalic primordial dwarfism disorder. Hitherto, the clinical manifestation of ATR deficiency has been attributed to its canonical role in DNA damage response signalling following replication fork stalling/collapse. Here, we show that ATR regulates cilia-dependent signalling in a manner that can be uncoupled from its function during replication. ATR-depleted or patient-derived ATR-SS cells form cilia of slightly reduced length but are dramatically impaired in cilia-dependent signalling functions, including growth factor and Sonic hedgehog signalling. To better understand the developmental impact of ATR loss of function, we also used zebrafish as a model. Zebrafish embryos depleted of Atr resembled ATR-SS morphology, showed a modest but statistically significant reduction in cilia length and other morphological features indicative of cilia dysfunction. Additionally, they displayed defects in left-right asymmetry including ambiguous expression of southpaw, incorrectly looped hearts and randomized localization of internal organs including the pancreas, features typically conferred by cilia dysfunction. Our findings reveal a novel role for ATR in cilia signalling distinct from its canonical function during replication and strengthen emerging links between cilia function and development.