Neuronal migration defects in the Dreher (Lmx1a) mutant mouse:: Role of disorders of the glial limiting membrane
Neuronal migration defects in the Dreher (Lmx1a) mutant mouse:: Role of disorders of the glial limiting membrane
复制标题
DOI：
10.1093/cercor/11.6.498
复制
发表时间：
2001-06-01
期刊：
影响因子：
3.7
通讯作者：
Copp, AJ
中科院分区：
文献类型：
--
作者：
Costa, C;Harding, B;Copp, AJ
Dreher（dr '）是新发现的LIM同源盒基因Lmx 1a中的常染色体隐性突变。纯合突变体表型包括大脑皮层、小脑和海马中的错位神经元（异位症），其模拟人类神经元迁移障碍谱的轻度末端。异位神经元主要位于dr'纯合子大脑半球内细胞稀疏的I层。Neu-N免疫染色证实了这些异位细胞的神经元性质，而溴脱氧尿苷出生日期显示，错位的神经元主要是在皮质生成的晚期阶段（E15-E17）产生的，这表明了注定为第二层的神经元过度迁移。层粘连蛋白的免疫组织化学和网硬蛋白纤维的染色揭示了特异性覆盖异位神经元区域的神经胶质界膜的破坏，因子VIII（von Willebrand因子）染色显示与碎裂的神经胶质界膜相关的第I层中的异常血管网络。I层星形胶质细胞，识别胶质细胞酸性蛋白的免疫染色，表现出其端足的碎片胶质细胞界膜的附件。我们认为胶质界膜的破坏是德雷尔异位神经元发病机制的核心，可能是通过缺陷的放射状胶质细胞引导的神经元迁移。
Dreher (dr') is an autosomal recessive mutation in the newly identified LIM homeobox gene, Lmx1a. The homozygous mutant phenotype includes misplaced neurons (heterotopia) in the cerebral cortex, cerebellum and hippocampus, which mimic the mild end of the spectrum of neuronal migration disorders in humans. Heterotopic neurons are found mainly in the normally cell-sparse layer I within the cerebral hemispheres of dr' homozygotes. Neu-N immunostaining confirms the neuronal nature of these heterotopic cells, while bromodeoxyuridine-birthdating shows that the misplaced neurons are generated predominantly during the late stages of corticogenesis (E15-E17), suggesting an over-migration of neurons destined for layer II. Immunohistochemistry for laminin, and staining of reticulin fibres, reveals disruption of the glial limiting membrane specifically overlying the areas of heterotopic neurons, Factor VIII (von Willebrand factor) staining shows an abnormal vascular network in layer I, associated with the fragmented glial limiting membrane. Layer I astrocytes, recognized by immunostaining for glial fibrillary acidic protein, exhibit attachment of their end foot to the fragmented glial limiting membrane. We suggest that disruption of the glial limiting membrana is central to the pathogenesis of heterotopic neurons in dreher, perhaps via defective radial glial-guided neuronal migration.