Department of Morphological Neural Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Development. 2011 Nov;138(22):4979-90. doi: 10.1242/dev.068155.
During corticogenesis, the regulation of neuronal migration is crucial for the functional organization of the neocortex. Glutamatergic neurons are major excitatory components of the mammalian neocortex. In order to elucidate the specific molecular mechanisms underlying their development, we used single-cell microarray analysis to screen for mouse genes that are highly expressed in developing glutamatergic neurons. We identified dpy-19-like 1 (Dpy19l1), a homolog of C. elegans dpy-19, which encodes a putative multi-transmembrane protein shown to regulate directed migration of Q neuroblasts in C. elegans. At embryonic stages Dpy19l1 is highly expressed in glutamatergic neurons in the mouse cerebral cortex, whereas in the subpallium, where GABAergic neurons are generated, expression was below detectable levels. Downregulation of Dpy19l1 mediated by shRNA resulted in defective radial migration of glutamatergic neurons in vivo, which was restored by the expression of shRNA-insensitive Dpy19l1. Many Dpy19l1-knockdown cells were aberrantly arrested in the intermediate zone and the deep layer and, additionally, some extended single long processes towards the pial surface. Furthermore, we observed defective radial migration of bipolar cells in Dpy19l1-knockdown brains. Despite these migration defects, these cells correctly expressed Cux1, which is a marker for upper layer neurons, suggesting that Dpy19l1 knockdown results in migration defects but does not affect cell type specification. These results indicate that Dpy19l1 is required for the proper radial migration of glutamatergic neurons, and suggest an evolutionarily conserved role for the Dpy19 family in neuronal migration.
在皮质发生过程中，神经元迁移的调节对于新皮层的功能组织至关重要。谷氨酸能神经元是哺乳动物新皮层的主要兴奋性成分。为了阐明其发育的特定分子机制，我们使用单细胞微阵列分析筛选在发育中的谷氨酸能神经元中高度表达的小鼠基因。我们鉴定了 dpy-19 样 1（Dpy19l1），它是秀丽隐杆线虫 dpy-19 的同源物，编码一种假定的多跨膜蛋白，被证明可以调节秀丽隐杆线虫 Q 神经母细胞的定向迁移。在胚胎期，Dpy19l1 在小鼠大脑皮层中的谷氨酸能神经元中高度表达，而在 GABA 能神经元产生的副皮质中，表达水平低于检测水平。通过 shRNA 下调 Dpy19l1 导致体内谷氨酸能神经元的放射状迁移缺陷，通过表达对 shRNA 不敏感的 Dpy19l1 可恢复。许多 Dpy19l1 敲低细胞在中间区和深层区异常停滞，此外，一些细胞还向软脑膜表面延伸单个长突起。此外，我们观察到 Dpy19l1 敲低脑中的双极细胞的放射状迁移缺陷。尽管存在这些迁移缺陷，但这些细胞正确表达了 Cux1，它是上层神经元的标志物，这表明 Dpy19l1 敲低导致迁移缺陷，但不影响细胞类型特异性。这些结果表明 Dpy19l1 是谷氨酸能神经元正确放射状迁移所必需的，并表明 Dpy19 家族在神经元迁移中的作用具有进化保守性。
