Distinct functions of glial and neuronal dystroglycan in the developing and adult mouse brain.
Distinct functions of glial and neuronal dystroglycan in the developing and adult mouse brain.
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胶质细胞和神经元肌营养不良聚糖在发育中和成年小鼠大脑中的独特功能。
DOI：
10.1523/jneurosci.3247-10.2010
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发表时间：
2010-10-27
期刊：
影响因子：
--
通讯作者：
Campbell KP
中科院分区：
文献类型：
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作者：
Satz JS;Ostendorf AP;Hou S;Turner A;Kusano H;Lee JC;Turk R;Nguyen H;Ross-Barta SE;Westra S;Hoshi T;Moore SA;Campbell KP
鹅卵石（II 型）无脑畸形和智力低下是先天性肌营养不良症的典型特征，其中包括沃克-瓦尔堡综合征、肌眼脑病和福山型先天性肌营养不良症。尽管大多数临床病例在遗传学上是不确定的，但已鉴定出一些致病基因，它们编码肌营养不良聚糖生物合成途径中已知或推定的糖基转移酶。在这里，我们测试了脑特异性删除肌营养不良聚糖的效果，并显示了神经元和神经胶质肌营养不良聚糖的不同功能。全脑中肌营养不良聚糖的缺失产生了神经胶质/神经元异位，类似于鹅卵石无脑畸形中的大脑皮层畸形。在野生型小鼠中，肌营养不良聚糖可稳定神经胶质限制细胞的基底膜，从而支持神经元迁移所需的皮质基础设施。该功能取决于细胞外肌营养不良聚糖的相互作用，因为缺乏肌营养不良聚糖细胞内结构域的转基因小鼠的大脑皮层发育正常。此外，在神经元特异性删除肌营养不良聚糖的小鼠中，前脑组织发生得以保留，但海马的长期增强作用减弱，就像 Largemyd 小鼠的情况一样，其中肌营养不良聚糖的糖基化被破坏。我们的研究结果提供了遗传证据，表明神经元肌营养不良聚糖在突触可塑性中发挥作用，并且神经胶质肌营养不良聚糖参与前脑发育。因此，中枢神经系统不同细胞类型中肌营养不良聚糖糖基化的差异可能导致中枢神经系统中肌营养不良聚糖功能的多样性，以及II型无脑畸形的广泛临床谱。
Cobblestone (type II) lissencephaly and mental retardation are characteristic features of a subset of congenital muscular dystrophies that include Walker-Warburg Syndrome, Muscle-Eye-Brain disease, and Fukuyama-type congenital muscular dystrophy. Although the majority of clinical cases are genetically undefined, several causative genes have been identified that encode known or putative glycosyltransferases in the biosynthetic pathway of dystroglycan. Here we test the effects of brain-specific deletion of dystroglycan, and show distinct functions for neuronal and glial dystroglycan. Deletion of dystroglycan in the whole brain produced glial/neuronal heterotopia resembling the cerebral cortex malformation in cobblestone lissencephaly. In wild-type mice, dystroglycan stabilizes the basement membrane of the glia limitans, thereby supporting the cortical infrastructure necessary for neuronal migration. This function depends on extracellular dystroglycan interactions, since the cerebral cortex developed normally in transgenic mice that lack the dystroglycan intracellular domain. Also, forebrain histogenesis was preserved in mice with neuron-specific deletion of dystroglycan, but hippocampal long-term potentiation was blunted, as is also the case in the Largemyd mouse, in which dystroglycan glycosylation is disrupted. Our findings provide genetic evidence that neuronal dystroglycan plays a role in synaptic plasticity and that glial dystroglycan is involved in forebrain development. Differences in dystroglycan glycosylation in distinct cell types of the CNS may therefore contribute to the diversity of dystroglycan function in the CNS, as well as to the broad clinical spectrum of type II lissencephalies.