Over-expression of the chondroitin sulphate proteoglycan versican is associated with defective neural crest migration in the Pax3 mutant mouse (splotch)
Over-expression of the chondroitin sulphate proteoglycan versican is associated with defective neural crest migration in the Pax3 mutant mouse (splotch)
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DOI：
10.1016/s0925-4773(97)00151-2
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发表时间：
1997-12-01
影响因子：
2.6
通讯作者：
Copp, AJ
中科院分区：
文献类型：
--
作者：
Henderson, DJ;Ybot-Gonzalez, P;Copp, AJ
携带Pax3基因突变的Splotch小鼠在纯合子中表现出与神经脊相关的异常，包括色素缺失、背根神经节减少或缺失以及心脏流出道分离失败。尽管Splotch神经脊细胞不能在靶组织中定植，但它们在体内启动了迁移，并在体外表现出与野生型神经脊细胞一样的迁移，这表明Splotch神经脊细胞的异常可能不是存在于神经脊细胞本身，而是它们迁移所通过的细胞外环境。我们检测了编码细胞外基质分子的基因在Sp(2H)纯合子胚胎中的表达，发现在神经脊细胞迁移的途径中，硫酸软骨素蛋白多糖的转录本明显过度表达。利用钙粘蛋白-6的表达作为神经脊的标记物表明，在Sp(2H)纯合子的神经管外侧间充质和下鳃弓中，versican表达的上调与迁移的神经脊细胞的缺失之间存在显著的相关性。在正常胚胎中，Pax3和verscan具有互斥的表达模式，而在Sp(2H)纯合子中，在正常表达Pax3的区域中，verscan通常是过度表达的。Verscan和其他硫酸软骨素蛋白多糖一样，不允许神经脊细胞在体外迁移，我们认为该分子的过度表达会导致斑点胚胎中神经脊细胞迁移的停止。Pax3可能在正常发育过程中负向调节verscan的表达，从而引导神经脊细胞进入它们的迁移途径。(C)1997年爱思唯尔爱尔兰科学有限公司。
Splotch mice, which harbour mutations in the Pax3 gene, exhibit neural crest-related abnormalities including pigmentation defects, reduced or absent dorsal root ganglia and failure of cardiac outflow tract septation in homozygotes. Although splotch neural crest cells fail to colonise target tissues, they initiate migration in vivo and appear to migrate as well as wild type neural crest cells in vitro, suggesting that the neural crest abnormality in splotch may reside not in the neural crest cells themselves, but rather in the extracellular environment through which they migrate. We have examined the expression of genes encoding extracellular matrix molecules in Sp(2H) homozygous embryos and find a marked over-expression of transcripts for the chondroitin sulphate proteoglycan versican in the pathways of neural crest cell migration. Use of cadherin-6 expression as a marker for neural crest demonstrates a striking correlation between up-regulation of versican expression and absence of migrating neural crest cells, both in the mesenchyme lateral to the neural tube and in the lower branchial arches of Sp(2H) homozygotes. Pax3 and versican have mutually exclusive expression patterns in normal embryos whereas, in Sp(2H) homozygotes, versican is generally over-expressed with 'infilling' in regions that would normally express functional Pax3. Versican, like other chondroitin sulphate proteoglycans, is non-permissive for migration of neural crest cells in vitro, and we suggest that over-expression of this molecule leads to the arrest of neural crest cell migration in splotch embryos. Pax3 may serve to negatively regulate versican expression during normal development, thereby guiding neural crest cells into their pathways of migration. (C) 1997 Elsevier Science Ireland Ltd.