Fras1, a basement membrane-associated protein mutated in Fraser syndrome, mediates both the initiation of the mammalian kidney and the integrity of renal glomeruli.
Fras1, a basement membrane-associated protein mutated in Fraser syndrome, mediates both the initiation of the mammalian kidney and the integrity of renal glomeruli.
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DOI：
10.1093/hmg/ddn297
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发表时间：
2008-12-15
影响因子：
3.5
通讯作者：
Woolf AS
中科院分区：
文献类型：
--
作者：
Pitera JE;Scambler PJ;Woolf AS
FRAS 1在一些患有弗雷泽综合征（FS）的个体中发生突变，编码的蛋白质在胚胎表皮细胞中表达，定位于基底膜（BM）。FS患者的并指和隐眼是皮肤脆性的后遗症，但相关的肾脏畸形的基础尚不清楚。我们证明，Fras 1表达的分支输尿管芽（UB），和肾发育不全发生在纯合子的Fras 1无效突变的水泡（BL）小鼠的C57 BL 6 J背景。在体内，BL/BL芽不能侵入后肾间充质，后肾间充质经历复旧，器官培养中重复的事件。胶质细胞源性神经营养因子和生长分化因子11的表达在体内的BL/BL肾原基中是有缺陷的，而在培养中，添加任一生长因子恢复芽侵入间质。突变体原基也表现出Hoxd 11和Six 2转录因子的表达不足，而骨形态发生蛋白4（一种抗分支分子）的活性上调。在野生型中，Fras 1也由新生肾单位表达。胎儿肾小球足细胞表达Fras 1转录本和Fras 1免疫定位在肾小球BM样模式。在混合背景下，bl突变体，以及bl和my（另一种水泡株）的复合突变体，有时能存活到成年期。这些小鼠有两个肾脏，其中包含具有扰动的nephrin、podocin、整合素α3和纤连蛋白表达的肾小球亚群。因此，Fras 1蛋白包被分支UB上皮细胞，并在间充质/上皮转化后的肾单位谱系中显著上调。Fras 1缺陷导致芽和间充质之间的相互作用缺陷，与关键肾生成分子的表达紊乱相关。此外，Fras 1也可能是正常肾小球形成所必需的。
FRAS1 is mutated in some individuals with Fraser syndrome (FS) and the encoded protein is expressed in embryonic epidermal cells, localizing in their basement membrane (BM). Syndactyly and cryptophthalmos in FS are sequelae of skin fragility but the bases for associated kidney malformations are unclear. We demonstrate that Fras1 is expressed in the branching ureteric bud (UB), and that renal agenesis occurs in homozygous Fras1 null mutant blebbed (bl) mice on a C57BL6J background. In vivo, the bl/bl bud fails to invade metanephric mesenchyme which undergoes involution, events replicated in organ culture. The expression of glial cell line-derived neurotrophic factor and growth-differentiation factor 11 was defective in bl/bl renal primordia in vivo, whereas, in culture, the addition of either growth factor restored bud invasion into the mesenchyme. Mutant primordia also showed deficient expression of Hoxd11 and Six2 transcription factors, whereas the activity of bone morphogenetic protein 4, an anti-branching molecule, was upregulated. In wild types, Fras1 was also expressed by nascent nephrons. Foetal glomerular podocytes expressed Fras1 transcripts and Fras1 immunolocalized in a glomerular BM-like pattern. On a mixed background, bl mutants, and also compound mutants for bl and my, another bleb strain, sometimes survive into adulthood. These mice have two kidneys, which contain subsets of glomeruli with perturbed nephrin, podocin, integrin α3 and fibronectin expression. Thus, Fras1 protein coats branching UB epithelia and is strikingly upregulated in the nephron lineage after mesenchymal/epithelial transition. Fras1 deficiency causes defective interactions between the bud and mesenchyme, correlating with disturbed expression of key nephrogenic molecules. Furthermore, Fras1 may also be required for the formation of normal glomeruli.
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跨跨性发育中的凋亡。
DOI：
10.1083/jcb.119.5.1327
发表时间：
1992-12
期刊：
The Journal of cell biology
影响因子：
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作者：
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通讯作者：
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影响因子：
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影响因子：
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影响因子：
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作者：
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DOI：
10.1073/pnas.0601011103
发表时间：
2006-08-08
影响因子：
11.1
作者：
Kiyozumi, Daiji;Sugimoto, Nagisa;Sekiguchi, Kiyotoshi
通讯作者：
Sekiguchi, Kiyotoshi