A reevaluation of X-irradiation-induced phocomelia and proximodistal limb patterning
A reevaluation of X-irradiation-induced phocomelia and proximodistal limb patterning
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DOI：
10.1038/nature08117
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发表时间：
2009-07-16
期刊：
影响因子：
64.8
通讯作者：
Tabin, Clifford J.
中科院分区：
文献类型：
--
作者：
Galloway, Jenna L.;Delgado, Irene;Tabin, Clifford J.
缺肢畸形是一种毁灭性的、罕见的先天性肢体畸形，患者的长骨比正常人短，肢体的上半部分受影响最严重。在极端情况下，手或手指直接附着在肩膀上，而最近端的部分（最靠近肩膀的部分）完全缺失。这种疾病以前以常染色体隐性遗传和散发性形式存在，在20世纪60年代初，由于药物沙利度胺的悲惨毒理学作用，发病率显着增加，沙利度胺曾作为轻度镇静剂开处方（1,2）。这种人类出生缺陷在暴露于x射线照射的发育中的小鸡肢体芽中被模仿（3-5）。x射线照射(5)和沙利度胺诱导的光秃（5,6）都被解释为进展区模型背景下的模式缺陷，该模型指出细胞的近端远端身份是由在被称为“进展区”的远端肢体区域停留的时间长短决定的(7)。事实上，x射线诱导光秃的研究已经成为支持进展区模型有效性的两大实验证据之一。在这里，结合分子分析和鸡的谱系追踪，我们表明x射线诱导的光秃从根本上来说不是一种模式缺陷，而是骨骼祖细胞的时间依赖性损失的结果。由于骨骼凝结从肩部到手指（从近端到远端方向），在早期暴露于辐射的肢芽中，近端元素受到的影响不同。这一结论改变了考虑沙利度胺和其他形式光秃影响的框架，表明其病因可能不在于图案化过程中的缺陷，而在于祖细胞的存活和分化。此外，分子证据表明，近端远端模式不受x射线照射后的影响，并不支持进展区模型的预测。
Phocomelia is a devastating, rare congenital limb malformation in which the long bones are shorter than normal, with the upper portion of the limb being most severely affected. In extreme cases, the hands or fingers are attached directly to the shoulder and the most proximal elements (those closest to the shoulder) are entirely missing. This disorder, previously known in both autosomal recessive and sporadic forms, showed a marked increase in incidence in the early 1960s due to the tragic toxicological effects of the drug thalidomide, which had been prescribed as a mild sedative(1,2). This human birth defect is mimicked in developing chick limb buds exposed to X-irradiation(3-5). Both X-irradiation(5) and thalidomide-induced phocomelia(5,6) have been interpreted as patterning defects in the context of the progress zone model, which states that a cell's proximodistal identity is determined by the length of time spent in a distal limb region termed the 'progress zone'(7). Indeed, studies of X-irradiation-induced phocomelia have served as one of the two major experimental lines of evidence supporting the validity of the progress zone model. Here, using a combination of molecular analysis and lineage tracing in chick, we show that X-irradiation-induced phocomelia is fundamentally not a patterning defect, but rather results from a time-dependent loss of skeletal progenitors. Because skeletal condensation proceeds from the shoulder to fingers (in a proximal to distal direction), the proximal elements are differentially affected in limb buds exposed to radiation at early stages. This conclusion changes the framework for considering the effect of thalidomide and other forms of phocomelia, suggesting the possibility that the aetiology lies not in a defect in the patterning process, but rather in progenitor cell survival and differentiation. Moreover, molecular evidence that proximodistal patterning is unaffected after X-irradiation does not support the predictions of the progress zone model.