Loss of Col3a1, the gene for Ehlers-Danlos syndrome type IV, results in neocortical dyslamination.
Loss of Col3a1, the gene for Ehlers-Danlos syndrome type IV, results in neocortical dyslamination.
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DOI：
10.1371/journal.pone.0029767
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Piao X
中科院分区：
文献类型：
--
作者：
Jeong SJ;Li S;Luo R;Strokes N;Piao X
新近发现，III型胶原是IV型Ehler-Danlos综合征(EDS)基因的编码蛋白，是软脑膜基底膜(BM)的主要成分之一，是GPR56的配体。GPR56基因突变会导致一种严重的人类大脑畸形，称为双侧额顶顶多小脑回，其中神经元通过BM转移，导致严重的精神发育迟滞和频繁的癫痫发作。为了进一步确定Col3a1基因敲除小鼠的脑表型，我们进行了详细的组织学分析。我们在Col3a1−/−小鼠脑中观察到一种鹅卵石样的皮质畸形，伴有BM破裂和边缘区异位。令人惊讶的是，软脑膜BM在发育早期似乎完好无损，但早在胚胎11.5天就开始，观察到明显的BM缺陷并伴有神经元过度迁移。虽然脑膜成纤维细胞表达III型胶原，但Col3a1−/−成纤维细胞没有明显的缺陷。此外，α-dystroglan在COL3a1−/−小鼠体内的表达和翻译后修饰没有受到干扰。基于先前发现COL3A1突变导致IV型EDS，我们的研究指出了结缔组织疾病和脑畸形之间可能存在的一种共同的病理途径。
It has recently been discovered that Collagen III, the encoded protein of the type IV Ehlers-Danlos Syndrome (EDS) gene, is one of the major constituents of the pial basement membrane (BM) and serves as the ligand for GPR56. Mutations in GPR56 cause a severe human brain malformation called bilateral frontoparietal polymicrogyria, in which neurons transmigrate through the BM causing severe mental retardation and frequent seizures. To further characterize the brain phenotype of Col3a1 knockout mice, we performed a detailed histological analysis. We observed a cobblestone-like cortical malformation, with BM breakdown and marginal zone heterotopias in Col3a1 −/− mouse brains. Surprisingly, the pial BM appeared intact at early stages of development but starting as early as embryonic day (E) 11.5, prominent BM defects were observed and accompanied by neuronal overmigration. Although collagen III is expressed in meningeal fibroblasts (MFs), Col3a1 −/− MFs present no obvious defects. Furthermore, the expression and posttranslational modification of α-dystroglycan was undisturbed in Col3a1 −/− mice. Based on the previous finding that mutations in COL3A1 cause type IV EDS, our study indicates a possible common pathological pathway linking connective tissue diseases and brain malformations.
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