Conditional knockout of protein O-mannosyltransferase 2 reveals tissue-specific roles of O-mannosyl glycosylation in brain development.
Conditional knockout of protein O-mannosyltransferase 2 reveals tissue-specific roles of O-mannosyl glycosylation in brain development.
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DOI：
10.1002/cne.22572
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发表时间：
2011-05-01
影响因子：
2.5
通讯作者：
Zhang, Peng
中科院分区：
文献类型：
--
作者：
Hu, Huaiyu;Li, Jing;Gagen, Christine S.;Gray, Noel W.;Zhang, Zhen;Qi, Yue;Zhang, Peng
关键词：
脑膜在正常脑发育过程中产生必要的信号分子和脑基底膜的主要蛋白质成分。由o -甘露糖基化相关基因突变引起的先天性肌营养不良（CMDs）患者脑基底膜破坏是神经异位的基础。在哺乳动物中，o -甘露糖基聚糖的生物合成是由相互不可缺少的蛋白质o -甘露糖基转移酶1和2 （POMT1和2）的复合体启动的。为了研究o -甘露糖基化在大脑发育中的作用，我们生成了一个POMT2条件等位基因。由于Reichert膜缺陷，POMT2无合子性导致胚胎致死。脑特异性的POMT2缺失导致α-三聚糖酐（DG）的低糖基化，并破坏层粘连蛋白的结合活性。POMT2缺失对大脑发育的影响取决于时间，因为更早的缺失会导致更严重的表型。观察到新皮层神经元过度迁移和小脑颗粒细胞迁移失败等多种脑畸形。免疫荧光染色和透射电镜显示，这些迁移缺陷与枕基底膜的破坏密切相关。有趣的是，脑膜（和血管）中的POMT2缺失并没有破坏新皮层的发育。因此，正常的大脑发育需要神经组织中的蛋白o -甘露糖基化活性，而不是脑膜。这些结果表明基因治疗应该针对神经组织而不是脑膜。
The meninges produce essential signaling molecules and major protein components of the pial basement membrane during normal brain development. Disruptions in the pial basement membrane underlie neural ectopia seen in those congenital muscular dystrophies (CMDs) caused by mutations in genes involved in O-mannosyl glycosylation. In mammals, biosynthesis of O-mannosyl glycans is initiated by a complex of mutually indispensable protein O-mannosyltransferases 1 and 2 (POMT1 and 2). To study the roles of O-mannosylation in brain development we generated a conditional allele of POMT2. POMT2 nulllizygosity resulted in embryonic lethality because of a defective Reichert's membrane. Brain-specific deletion of POMT2 resulted in hypoglycosylation of α-dystroglycan (DG) and abolished laminin binding activity. The effect of POMT2 deletion on brain development was dependent on timing, as earlier deletion resulted in more severe phenotypes. Multiple brain malformations including overmigration of neocortical neurons and migration failure of granule cells in the cerebellum were observed. Immunofluorescence staining and transmission electron microscopy revealed that these migration defects were closely associated with disruptions in the pial basement membrane. Interestingly, POMT2 deletion in the meninges (and blood vessels) did not disrupt the development of the neocortex. Thus, normal brain development requires protein O-mannosylation activity in neural tissue but not the meninges. These results suggest that gene therapy should be directed to the neural tissue instead of the meninges.
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DOI：
10.1083/jcb.122.4.809
发表时间：
1993-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ervasti JM;Campbell KP
通讯作者：
Campbell KP
影响因子：
5.3
作者：
DArcangelo, G;Nakajima, K;Curran, T
通讯作者：
Curran, T
影响因子：
3.5
作者：
Brockington, M;Yuva, Y;Muntoni, F
通讯作者：
Muntoni, F
影响因子：
9.8
作者：
Brockington, M;Blake, DJ;Muntoni, F
通讯作者：
Muntoni, F
影响因子：
9.2
作者：
Georges-Labouesse, E;Mark, M;Gansmüller, A
通讯作者：
Gansmüller, A