Glial scaffold required for cerebellar granule cell migration is dependent on dystroglycan function as a receptor for basement membrane proteins.
Glial scaffold required for cerebellar granule cell migration is dependent on dystroglycan function as a receptor for basement membrane proteins.
复制标题
小脑颗粒细胞迁移所需的神经胶质支架取决于多糖果作为基底膜蛋白的受体。
DOI：
10.1186/2051-5960-1-58
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发表时间：
2013-09-06
影响因子：
7.1
通讯作者：
Moore SA
中科院分区：
文献类型：
--
作者：
Nguyen H;Ostendorf AP;Satz JS;Westra S;Ross-Barta SE;Campbell KP;Moore SA
鹅卵石无脑畸形是一种严重的神经元迁移障碍，与先天性肌营养不良症（CMD），如沃克-沃伯格综合征，肌肉-眼-脑疾病，福山型CMD。在这些严重形式的肌营养不良聚糖病中，肌营养不良和其他组织病理学是由参与α-肌营养不良聚糖的O-连接糖基化的基因突变引起的。虽然小脑发育不良是营养不良性聚糖病的常见特征，但其发病机制尚未得到彻底研究。在这里，我们评估的作用，肌营养不良蛋白聚糖在小脑发育。脑选择性缺失肌营养不良蛋白聚糖不影响整体小脑生长，但会导致与胶质细胞界膜破坏和颗粒细胞异位相关的畸形，这些畸形重现了肌营养不良蛋白聚糖病患者中发现的表型。这些小鼠的小脑病理学直到出生时才明显，即使在胚胎发生的第二周肌营养不良蛋白聚糖丢失。胶质界膜破坏、Bergmann胶质解体和异位的严重程度和空间分布在出生后发育过程中加剧。当小脑发育完成时，这些相同部位的星形胶质细胞增生变得突出。有趣的是，有空间异质性的胶质细胞界和颗粒神经元迁移缺陷，使小叶IV-V和VI的提示。发育病理学的全谱是由Bergmann胶质细胞的肌营养不良蛋白聚糖的损失引起的，因为颗粒细胞特异性肌营养不良蛋白聚糖缺失和浦肯野细胞特异性肌营养不良蛋白聚糖缺失都不会导致类似的病理学。这些数据说明了在放射状/Bergmann神经胶质细胞，而不是神经元，正常小脑组织发生的dystroglycan功能的重要性。病理学的空间异质性表明对肌营养不良蛋白聚糖的依赖性是不均匀的。
Cobblestone lissencephaly is a severe neuronal migration disorder associated with congenital muscular dystrophies (CMD) such as Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama-type CMD. In these severe forms of dystroglycanopathy, the muscular dystrophy and other tissue pathology is caused by mutations in genes involved in O-linked glycosylation of alpha-dystroglycan. While cerebellar dysplasia is a common feature of dystroglycanopathy, its pathogenesis has not been thoroughly investigated. Here we evaluate the role of dystroglycan during cerebellar development. Brain-selective deletion of dystroglycan does not affect overall cerebellar growth, yet causes malformations associated with glia limitans disruptions and granule cell heterotopia that recapitulate phenotypes found in dystroglycanopathy patients. Cerebellar pathology in these mice is not evident until birth even though dystroglycan is lost during the second week of embryogenesis. The severity and spatial distribution of glia limitans disruption, Bergmann glia disorganization, and heterotopia exacerbate during postnatal development. Astrogliosis becomes prominent at these same sites by the time cerebellar development is complete. Interestingly, there is spatial heterogeneity in the glia limitans and granule neuron migration defects that spares the tips of lobules IV-V and VI. The full spectrum of developmental pathology is caused by loss of dystroglycan from Bergmann glia, as neither granule cell- nor Purkinje cell-specific deletion of dystroglycan results in similar pathology. These data illustrate the importance of dystroglycan function in radial/Bergmann glia, not neurons, for normal cerebellar histogenesis. The spatial heterogeneity of pathology suggests that the dependence on dystroglycan is not uniform.