Mouse orthologue of ARX, a gene mutated in several X-linked forms of mental retardation and epilepsy, is a marker of adult neural stem cells and forebrain GABAergic neurons
Mouse orthologue of ARX, a gene mutated in several X-linked forms of mental retardation and epilepsy, is a marker of adult neural stem cells and forebrain GABAergic neurons
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DOI：
10.1002/dvdy.20164
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发表时间：
2004-11-01
影响因子：
2.5
通讯作者：
Broccoli, V
中科院分区：
文献类型：
--
作者：
Colombo, E;Galli, R;Broccoli, V
人类ARX基因的突变表现出异常的异质性临床表现，包括综合征和非综合征性精神发育迟滞、肌阵挛性癫痫伴痉挛和无脑伴异常生殖器，这些被认为是由构建前中枢神经系统结构的胚胎机制受损引起的。在这里，我们表明，小鼠直系同源Arx具有高度动态的表达模式，在早期形成的前脑囊泡和后来的重大事件的神经迁移和细胞类型的规范。早期，Arx基因在前脑原基中被特异性激活。之后，Arx表达局限于端脑囊泡，并在神经节隆起的苍白球下结构分化过程中增强，与Dlx2，Dlx5和Gad1转录结构域重叠。切向迁移的神经元到达皮质板也Arx阳性在所有胚胎阶段分析。RNA-蛋白质共标记染色显示，Arx表达维持在成熟的皮质中间神经元中，这表明其参与了γ-氨基丁酸（GABA）能神经元的不同功能，这些神经元定居在成年大脑皮层中。最后，Arx的表达被检测到在前脑室下层的成人大脑，神经干细胞已被证明位于。感兴趣的是，Arx表达在从成人脑中提取的纯神经干细胞培养物的体外分化过程中高度上调。总之，这些发现表明Arx是参与将增殖的神经母细胞转化为GABA能神经元命运的基因。总之，我们的小鼠Arx表达数据为人类ARX突变多效性的令人困惑的复杂性提供了重要的进一步见解。(C)2004 Wiley-Liss，Inc.
Mutations in the human ARX gene show unusually heterogeneous clinical presentations, including syndromic and nonsyndromic mental retardation, myoclonic epilepsy with spasticity, and lissencephally with abnormal genitalia, that are believed to arise from an impairment of the embryonic mechanisms building the anterior central nervous system structures. Here, we show that the murine ortholog Arx has a highly dynamic expression pattern during both early shaping of the forebrain vesicle and later major events of neural migrations and cell-type specification. Early on, the Arx gene is specifically activated in anterior forebrain anlage. Afterward, Arx expression is confined to the telencephalic vesicles and is enhanced during differentiation of the subpallial structures of the ganglionic eminences, overlapping with Dlx2, Dlx5, and Gad1 transcriptional domains. Tangentially migrating neurons reaching the cortical plate are also Arx-positive at all embryonic stages analyzed. RNA-protein colabeling staining shows that Arx expression is maintained in the mature cortical interneurons, suggesting its involvement in the different functions of the gamma-aminobutyric acid (GABA)ergic neurons settled into the adult cerebral cortex. Finally, Arx expression is detected in the anterior subventricular layer of the adult brain, where neural stem cells have been shown to be located. Of interest, Arx expression is highly up-regulated during in vitro differentiation of pure neural stem cell cultures retrieved from adult brain. All together, these findings suggest Arx as a gene involved in the commitment of proliferating neuroblasts into a GABAergic neuronal fate. In conclusion, our mouse Arx expression data provide important further insights into the puzzling complexity of the human ARX mutation pleiotropy. (C) 2004 Wiley-Liss, Inc.