Genetic steps to organ laterality in zebrafish.
Genetic steps to organ laterality in zebrafish.
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DOI：
10.1002/cfg.74
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发表时间：
2001
影响因子：
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通讯作者：
Fishman, M C
中科院分区：
文献类型：
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作者：
Chen, J N;van Bebber, F;Goldstein, A M;Serluca, F C;Jackson, D;Childs, S;Serbedzija, G;Warren, K S;Mably, J D;Lindahl, P;Mayer, A;Haffter, P;Fishman, M C
所有内脏器官在左右轴上都是不对称的。在此我们报道一项遗传筛选，以发现扰乱器官左右不对称性的突变。我们特别关注的是器官在达到其左右不对称位置时是否以及如何相互关联。我们通过ENU诱变产生突变，并使用一组能显示心脏、肠道、肝脏和胰腺早期原基的探针检测F3代后代。在检查的750个基因组中，我们分离出7种隐性突变，这些突变影响一个或所有器官最早的左右定位。在所检查的胚胎阶段，这些突变在胚胎的其他部位均未引起明显缺陷。这与我们之前报道的那些突变（Chen等人，1997）形成对比，那些突变除了左右异常外，还会在原肠胚形成、身体形态或中线结构方面造成显著扰动。我们发现可以根据这些突变是否扰乱器官左右不对称性之间的关系对其进行分类。在1类突变中，所有器官都没有表现出任何左右不对称性。心脏不会向左偏移，早期心管中通常以左侧为主的BMP4仍然对称。肠道往往保持在中线位置。肝脏和胰腺经常出现显著的双侧重复。具有2类突变的胚胎具有器官类型的不对称性，但在任何给定的胚胎中，器官位置可能正常、反转或随机。3类突变揭示了一个迄今未被怀疑的基因，它选择性地影响心脏的左右不对称性。我们发现内脏器官的位置是由先前心脏偏移的方向所决定的。我们将此解释为表明正常情况下心脏和内脏器官的左右不对称性之间存在联系。我们认为，1类突变有效地消除了整体的左右不对称性信号，结果是器官位置实际上是对称的。具有2类突变的胚胎确实表现出器官之间的联系，但这种联系可能是反转的，这表明整体信号可能存在，但在一些胚胎中方向不正确。器官的左右不对称性决定可能像3类突变那样独立地受到扰动，这表明对于整体信号的接收和器官类型的解读存在不同的途径。
All internal organs are asymmetric along the left–right axis. Here we report a genetic screen to discover mutations which perturb organ laterality. Our particular focus is upon whether, and how, organs are linked to each other as they achieve their laterally asymmetric positions. We generated mutations by ENU mutagenesis and examined F3 progeny using a cocktail of probes that reveal early primordia of heart, gut, liver and pancreas. From the 750 genomes examined, we isolated seven recessive mutations which affect the earliest left–right positioning of one or all of the organs. None of these mutations caused discernable defects elsewhere in the embryo at the stages examined. This is in contrast to those mutations we reported previously (Chen et al., 1997) which, along with left–right abnormalities, cause marked perturbation in gastrulation, body form or midline structures. We find that the mutations can be classified on the basis of whether they perturb relationships among organ laterality. In Class 1 mutations, none of the organs manifest any left–right asymmetry. The heart does not jog to the left and normally leftpredominant BMP4 in the early heart tube remains symmetric. The gut tends to remain midline. There frequently is a remarkable bilateral duplication of liver and pancreas. Embryos with Class 2 mutations have organotypic asymmetry but, in any given embryo, organ positions can be normal, reversed or randomized. Class 3 reveals a hitherto unsuspected gene that selectively affects laterality of heart. We find that visceral organ positions are predicted by the direction of the preceding cardiac jog. We interpret this as suggesting that normally there is linkage between cardiac and visceral organ laterality. Class 1 mutations, we suggest, effectively remove the global laterality signals, with the consequence that organ positions are effectively symmetrical. Embryos with Class 2 mutations do manifest linkage among organs, but it may be reversed, suggesting that the global signals may be present but incorrectly orientated in some of the embryos. That laterality decisions of organs may be independently perturbed, as in the Class 3 mutation, indicates that there are distinctive pathways for reception and organotypic interpretation of the global signals.