Zebrafish Hagoromo mutants up-regulate fgf8 postembryonically and develop neuroblastoma.
Zebrafish Hagoromo mutants up-regulate fgf8 postembryonically and develop neuroblastoma.
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DOI：
10.1158/1541-7786.mcr-08-0555
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发表时间：
2009-06
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影响因子：
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通讯作者：
Lees JA
中科院分区：
文献类型：
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作者：
Amsterdam A;Lai K;Komisarczuk AZ;Becker TS;Bronson RT;Hopkins N;Lees JA
我们筛选了现有的收集斑马鱼插入突变体的癌症易感性的组织学检查杂合子在2岁。由于大多数突变体没有改变癌症易感性，这首次全面描述了成年斑马鱼的自发肿瘤谱和频率。此外，筛选确定了四个品系，每个品系携带Hagoromo的不同显性突变等位基因，这些等位基因先前与成人色素沉着缺陷有关，这些突变等位基因发展出组织学上类似于神经母细胞瘤的高转移率肿瘤。这些肿瘤显然是神经源性的，虽然他们不表达人神经母细胞瘤的特征性儿茶酚胺能神经元标记物。斑马鱼肿瘤是由于颅神经节内可能是神经前体的细胞群维持不当造成的。这些肿瘤通常保持较小，但它们可以变得高度侵袭性，最初沿着颅神经行进，并最终填充头部。这些肿瘤的发育起源非常类似于人类神经母细胞瘤。这四个突变的Hagoromo等位基因都含有病毒插入fbxw4基因，编码一个F盒WD 40结构域的蛋白质。然而，虽然一个等位基因明显降低了fbxw4 mRNA的水平，但其他三个插入对fbw4表达没有可检测的影响。相反，我们发现，所有四个突变的结果在胚胎后上调的相邻基因，成纤维细胞生长因子8（fgf8）。此外，fgf8在致瘤性病变中高度表达。虽然fgf8的过度表达与哺乳动物的乳腺癌和前列腺癌有关，但这项研究首次提供了fgf8失调可导致神经肿瘤的证据。
We screened an existing collection of zebrafish insertional mutants for cancer susceptibility by histological examination of heterozygotes at two years of age. As most mutants had no altered cancer predisposition, this provided the first comprehensive description of spontaneous tumor spectrum and frequency in adult zebrafish. Moreover, the screen identified four lines, each carrying a different dominant mutant allele of Hagoromo previously linked to adult pigmentation defects, which develop tumors with high penetrance that histologically resemble neuroblastoma. These tumors are clearly neural in origin, although they do not express catecholaminergic neuronal markers characteristic of human neuroblastoma. The zebrafish tumors result from inappropriate maintenance of a cell population within the cranial ganglia that are likely neural precursors. These neoplasias typically remain small but they can become highly aggressive, initially traveling along cranial nerves, and ultimately filling the head. The developmental origin of these tumors is highly reminiscent of human neuroblastoma. The four mutant Hagoromo alleles all contain viral insertions in the fbxw4 gene, which encodes an F-box WD40 domain containing protein. However, while one allele clearly reduced the levels of fbxw4 mRNA, the other three insertions have no detectable effect on fbw4 expression. Instead, we show that all four mutations result in the post-embryonic upregulation of the neighboring gene, fibroblast growth factor 8 (fgf8). Moreover, fgf8 is highly expressed in the tumorigenic lesions. While fgf8 overexpression is known to be associated with breast and prostate cancer in mammals, this study provides the first evidence that fgf8 misregulation can lead to neural tumors.