Basement membrane fragility underlies embryonic lethality in fukutin-null mice
Basement membrane fragility underlies embryonic lethality in fukutin-null mice
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DOI：
10.1016/j.nbd.2004.12.018
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发表时间：
2005-06-01
影响因子：
6.1
通讯作者：
Toda, T
中科院分区：
文献类型：
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作者：
Kurahashi, H;Taniguchi, M;Toda, T
福山型先天性肌营养不良症(FCMD)是由Fukuutin基因突变引起的，与神经元迁移缺陷引起的脑畸形有关。一些证据表明，Fukutin蛋白在细胞表面层粘连蛋白受体α-Dystroglan的O-甘露糖基部分的合成中起着关键作用。在这里，通过定向破坏同源小鼠的fukutin基因，我们证明了fukutin蛋白是必不可少的，因为纯合子缺失的胚胎在妊娠9.5周时死亡。Fukutin基因缺失的胚胎表现出表型多样性，其特征包括生长迟缓、卵筒折叠、母体红细胞渗入卵黄囊，以及外胚层中凋亡细胞数量增加。α-营养不良多糖对糖部分免疫反应性的丧失表明层粘连蛋白结合能力降低。超微结构分析显示基底膜(BMS)变薄和断裂。骨髓脆性可能是所有这些异常表型的基础，而维持骨髓功能可能需要在胚胎发育早期通过河豚毒素介导的α-营养不良聚糖的糖基化。(C)2005 Elsevier Inc.保留所有权利。
Fukuyama-type congenital muscular dystrophy (FCMD), associated with brain malformation due to defects in neuronal migration, is caused by mutations in fukutin. Several lines of evidence suggest that the fukutin protein plays a pivotal role in synthesis of O-mannosyl sugar moieties of alpha-dystroglycan, a cell surface laminin receptor. Here, through targeted disruption of the orthologous mouse fukutin gene, we show that the fukutin protein is essential, as homozygous-null embryos die by E9.5 of gestation. Fukutin-null embryos show phenotypic diversity, features of which include growth retardation, folding of the egg cylinder, leakage of maternal red blood cells into the yolk sac cavity, and an increased number of apoptotic cells in the ectoderm. Loss of immunoreactivity against sugar moieties in alpha-dystroglycan suggests a reduced laminin-binding capacity. Ultrastructural analysis shows thin and breached basement membranes (BMs). BM fragility may underlie all of these abnormal phenotypes, and maintenance of BM function may require fukutin-mediated glycosylation of alpha-dystroglycan early in embryonic development. (c) 2005 Elsevier Inc. All rights reserved.