Moore Steven A, Saito Fumiaki, Chen Jianguo, Michele Daniel E, Henry Michael D, Messing Albee, Cohn Ronald D, Ross-Barta Susan E, Westra Steve, Williamson Roger A, Hoshi Toshinori, Campbell Kevin P
Department of Pathology, The University of Iowa, Iowa City, Iowa 52242-1101, USA.
Nature. 2002 Jul 25;418(6896):422-5. doi: 10.1038/nature00838.
Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and Walker-Warburg syndrome are congenital muscular dystrophies (CMDs) with associated developmental brain defects. Mutations reported in genes of FCMD and MEB patients suggest that the genes may be involved in protein glycosylation. Dystroglycan is a highly glycosylated component of the muscle dystrophin-glycoprotein complex that is also expressed in brain, where its function is unknown. Here we show that brain-selective deletion of dystroglycan in mice is sufficient to cause CMD-like brain malformations, including disarray of cerebral cortical layering, fusion of cerebral hemispheres and cerebellar folia, and aberrant migration of granule cells. Dystroglycan-null brain loses its high-affinity binding to the extracellular matrix protein laminin, and shows discontinuities in the pial surface basal lamina (glia limitans) that probably underlie the neuronal migration errors. Furthermore, mutant mice have severely blunted hippocampal long-term potentiation with electrophysiologic characterization indicating that dystroglycan might have a postsynaptic role in learning and memory. Our data strongly support the hypothesis that defects in dystroglycan are central to the pathogenesis of structural and functional brain abnormalities seen in CMD.
福山型先天性肌营养不良(FCMD)、肌肉-眼-脑疾病(MEB)和沃克-沃尔堡综合征是伴有发育性脑缺陷的先天性肌营养不良(CMD)。在FCMD和MEB患者基因中报道的突变表明这些基因可能参与蛋白质糖基化。肌营养不良聚糖是肌肉肌营养不良蛋白-糖蛋白复合物中高度糖基化的成分,在脑中也有表达,但其功能尚不清楚。在此我们表明,在小鼠中脑选择性缺失肌营养不良聚糖足以导致类似CMD的脑畸形,包括大脑皮质分层紊乱、大脑半球和小脑小叶融合以及颗粒细胞异常迁移。缺乏肌营养不良聚糖的脑失去了与细胞外基质蛋白层粘连蛋白的高亲和力结合,并在软脑膜表面基膜(胶质界膜)出现连续性中断,这可能是神经元迁移错误的基础。此外,突变小鼠的海马长时程增强严重减弱,电生理特征表明肌营养不良聚糖可能在学习和记忆中具有突触后作用。我们的数据有力地支持了这样的假说,即肌营养不良聚糖缺陷是CMD中所见结构和功能性脑异常发病机制的核心。