Craniosynostosis and Multiple Skeletal Anomalies in Humans and Zebrafish Result from a Defect in the Localized Degradation of Retinoic Acid
Craniosynostosis and Multiple Skeletal Anomalies in Humans and Zebrafish Result from a Defect in the Localized Degradation of Retinoic Acid
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DOI：
10.1016/j.ajhg.2011.09.015
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发表时间：
2011-11-11
影响因子：
9.8
通讯作者：
Robertson, Stephen P.
中科院分区：
文献类型：
--
作者：
Laue, Kathrin;Pogoda, Hans-Martin;Robertson, Stephen P.
过量的外源性视黄酸（RA）已被充分证明在肢体和颅面骨骼中具有致畸作用。在这种情况下观察到的畸形包括颅缝早闭，这是一种常见的颅骨发育缺陷，发生率为1/2500，由颅缝过早融合引起。尽管有这些观察结果，RA在缝线形成过程中的生理作用尚未得到证实。在这里，我们提出的证据表明，RA信号的遗传基础上的改变干扰人类的发展。我们已经确定了编码RA降解酶CYP 26 B1的基因中的人类无效突变和亚型突变，这些突变导致骨骼和颅面异常，包括长骨融合、颅骨发育不全和颅缝早闭。对暴露于Cyp 26酶的化学抑制剂的鼠胚胎和Cyp 26 B1突变的斑马鱼系的分析表明，软骨内骨融合是由于软骨模板内关节形成的假定位点处的不受限制的软骨形成，而颅缝早闭是由成骨细胞分化缺陷引起的。骨分化的细胞标志物的超微结构分析、原位表达研究和体外定量RT-PCR实验表明，这些现象最可能的原因是异常的成骨细胞-骨细胞转变。这项工作揭示了RA在分割骨骼元素和维持颅缝通畅的生理作用。
Excess exogenous retinoic acid (RA) has been well documented to have teratogenic effects in the limb and craniofacial skeleton. Malformations that have been observed in this context include craniosynostosis, a common developmental defect of the skull that occurs in 1 in 2500 individuals and results from premature fusion of the cranial sutures. Despite these observations, a physiological role for RA during suture formation has not been demonstrated. Here, we present evidence that genetically based alterations in RA signaling interfere with human development. We have identified human null and hypomorphic mutations in the gene encoding the RA-degrading enzyme CYP26B1 that lead to skeletal and craniofacial anomalies, including fusions of long bones, calvarial bone hypoplasia, and craniosynostosis. Analyses of murine embryos exposed to a chemical inhibitor of Cyp26 enzymes and zebrafish lines with mutations in cyp26b1 suggest that the endochondral bone fusions are due to unrestricted chondrogenesis at the presumptive sites of joint formation within cartilaginous templates, whereas craniosynostosis is induced by a defect in osteoblastic differentiation. Ultrastructural analysis, in situ expression studies, and in vitro quantitative RT-PCR experiments of cellular markers of osseous differentiation indicate that the most likely cause for these phenomena is aberrant osteoblast-osteocyte transitioning. This work reveals a physiological role for RA in partitioning skeletal elements and in the maintenance of cranial suture patency.