Molecular Mechanism of Cortical Area Specification

1.哺乳动物新皮质发育出具有区域差异的层状组织，表现为胚胎阶段多个基因的表达。这些基因可能在区域细胞结构的形成中发挥重要作用，然而，到目前为止发现的基因数量还不足以解释这种复杂的过程。在这里，我们收集了E-16.5小鼠大脑皮质的内侧、背侧、外侧、吻侧和枕部五个区域，利用DNA微阵列进行了广泛的基因表达分析，成功地鉴定了背侧区域的7个基因，内侧区域的3个基因和外侧区域的3个基因。特别是，在背侧区域发现的所有七个基因都划分了皮质板中未来的躯体感觉和听觉区域，具有高吻侧-低尾内侧梯度。此外，神经肽Y的区域表达模式向嘴方向移动，层特异性被打乱了…在Pax6基因缺陷的小鼠中更多。我们的结果提供了关于胚胎晚期皮质板中区域表达基因亚类的新信息，这可能有助于理解新皮质区域化的分子机制。接下来，我们通过研究外周胡须图案在小鼠三叉神经体感投射脑干和丘脑的图案形成中的作用来挑战体感图案形成机制。通过用携带Shh的腺病毒感染胚胎表皮来操纵胡须图案。Shh的异位表达导致了额外的胡须的诱导和胡须的移位，这些胡须在组织学上是正常的。改变的胡须图案在脑干(桶状核：主亚核和内亚核)、丘脑(桶状核)和皮质(桶状核)中同形出现。这些结果强调了外周胡须图案在小鼠躯体感觉系统中脑干、丘脑和皮质的中央图案中的作用。最后，我们研究了发育中的FEZL缺陷小鼠的丘脑皮质和皮质逃逸通路(理研的Masahiko Hibi博士)。FEZ样蛋白(FEZ-like，FEZL)是一种转录抑制因子，选择性地在发育中的皮质深层表达。在正常小鼠中，皮质轴突和丘脑轴突在胚胎13.5天和胚胎14.5天在内囊中相遇，并在它们分别延伸到它们的目标丘脑和皮质时彼此成束。在FEZL缺陷小鼠中，大多数丘脑和皮质轴突在胚胎14.5岁时分别停止在内囊和大脑皮质下交界处。在前人研究的基础上，本研究认为FEZL缺陷小鼠丘脑皮质轴突的异常轨迹是由表达FEZL的皮质传出神经元的缺陷引起的。较少

1. The mammalian neocortex develops layer organizations with regional differences represented by expression of multiple genes at embryonic stages. These genes could play important roles in the formation of areal cyto-architecture, yet, the number of genes identified so far is not sufficient to explain such intricate processes. Here we collected five regions-the medial, dorsal, lateral, rostral and occipital from the dissected E 16.5 mouse cerebral cortex, performed extensive gene expression analysis using DNA microarray, and reached the successful identification of seven genes from the dorsal region, three genes from the medial region, and three genes from the lateral region. Particularly, all seven genes identified in the dorsal region demarcated the future somatosensory and auditory areas in the cortical plate with high rostrolateral-low caudomedial gradation. Furthermore, the regional expression pattern of NeuropeptideY was shifted rostral and the layer specificity was disorganized … More in the Pax6-deficient mice. Our results provide new information about a subclass of regionally expressed genes in the cortical plate at the late embryonic stage, which may help understand the molecular mechanisms of neocortical arealization.2. Next, we challenged the somatosensory patterning mechanism by investigating the role of a peripheral whisker pattern for the patterning of the mouse somatosensory trigeminal projection at the brainstem and thalamus. The whisker pattern was manipulated by infecting the embryonic epidermis with adenovirus harboring Shh. The ectopic expression of Shh led to the induction of extra whiskers and displacement of whiskers, where these whiskers were histologically normal. The altered whisker pattern was isomorphically represented in the brainstem (barrelette: subnuclei principalis and subnuclei interpolaris), thalamus (barreloid) and cortex (barrel). These results highlight the role of the peripheral whisker pattern for the central patterning of the brainstem, thalamus, and cortex in the mouse somatosensory system.3. Finally, we examined the thalamocortical and corticofugal pathway in developing Fezl-deficient mice (Dr. Masahiko Hibi at Riken). The fez-like (Fezl) protein is a transcriptional repressor selectively expressed in the deep layers of the developing cortex. In normal mice, cortical and thalamic axons meet in the internal capsule between embryonic day (E) 13.5 and E14.5 and fasciculate with each other as they extend to their targets, namely, the thalamus and cortex, respectively. In Fezl-deficient mice, most of the thalamic and cortical axons stop in the internal capsule and at the pallial-subpallial boundary, respectively, at E14.5. Based upon previous studies, the present study suggests that the aberrant trajectories of the thalamocortical axons in Fezl-deficient mice are caused by defects in the cortical efferent neurons that express Fezl. Less