Loss of Emx2 function leads to ectopic expression of Wnt1 in the developing telencephalon and cortical dysplasia
Loss of Emx2 function leads to ectopic expression of Wnt1 in the developing telencephalon and cortical dysplasia
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DOI：
10.1242/dev.00421
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发表时间：
2003-05-01
期刊：
影响因子：
4.6
通讯作者：
Rowitch, DH
中科院分区：
文献类型：
--
作者：
Ligon, KL;Echelard, Y;Rowitch, DH
软脑膜胶质神经元异位是皮质发育不良的一种局灶性类型，其中神经细胞异常迁移到大脑皮层和脑膜的浅层。这些异位经常被观察为中枢神经系统（CNS）畸形和癫痫患者大脑中的微观异常。先前的研究表明，编码同源结构域转录因子的 Emx2 的功能对于皮质前板的发育至关重要，皮质前板产生边缘区和亚板。然而，中枢神经系统发育过程中 EMX2 的转录靶标尚不清楚。我们报告说，Emx2(-/-) 小鼠中形成了相当于人类病变的软脑膜胶质神经元异位。此外，我们在胚胎顶板组织区和背侧端脑中观察到 Wnt1 的异位表达。为了确定这种 Wnt1 错误表达的表型后果，我们从 Wnt1 增强子中删除了一个假定的 EMX2 DNA 结合位点，并用它在发育中的小鼠中枢神经系统中错误表达 Wnt1。早在交配后 13.5 天就在转基因小鼠中检测到异位，这与径向神经元迁移早期阶段前板发育的缺陷一致。此外，我们观察到边缘区和亚板中 reelin 和 calretinin 阳性细胞群的弥漫性异常，类似于在 Emx2 缺失动物中观察到的情况。总而言之，这些发现表明 EMX2 是发育中的哺乳动物端脑中 Wnt1 表达的直接抑制因子。他们进一步表明，EMX2-Wnt1 相互作用对于哺乳动物大脑皮层中前板衍生物的正常发育至关重要。
Leptomeningeal glioneuronal heterotopias are a focal type of cortical dysplasia in which neural cells migrate aberrantly into superficial layers of the cerebral cortex and meninges. These heterotopias are frequently observed as microscopic abnormalities in the brains of individuals with central nervous system (CNS) malformations and epilepsy. Previous work has demonstrated that the function of Emx2, which encodes a homeodomain transcription factor, is essential for development of the cortical preplate, which gives rise to the marginal zone and subplate. However, transcriptional targets of EMX2 during CNS development are unknown. We report that leptomeningeal glioneuronal heterotopias form in Emx2(-/-) mice that are equivalent to human lesions. Additionally, we observed ectopic expression of Wnt1 in the embryonic roofplate organizer region and dorsal telencephalon. To determine the phenotypic consequences of such Wnt1 misexpression, we deleted a putative EMX2 DNA-binding site from the Wnt1 enhancer and used this to misexpress Wnt1 in the developing murine CNS. Heterotopias were detected in transgenic mice as early as 13.5 days postcoitum, consistent with a defect of preplate development during early phases of radial neuronal migration. Furthermore, we observed diffuse abnormalities of reelin- and calretinin-positive cell populations in the marginal zone and subplate similar to those observed in Emx2-null animals. Taken together, these findings indicate that EMX2 is a direct repressor of Wnt1 expression in the developing mammalian telencephalon. They further suggest that EMX2-Wnt1 interactions are essential for normal development of preplate derivatives in the mammalian cerebral cortex.