Development of Somatosensory Area

我们的研究目标是了解体感觉皮层功能发育的分子基础。我们采用了三种方法来实现这一研究目标。首先，皮层区域的发育经历了几个步骤。在早期前脑中，FGF8、Wnt和Shh等形态因子根据体轴呈梯度表达，并诱导一系列转录因子，进而决定前脑的区域特异性。其中一个区域特异性基因是钙粘蛋白6，它在产生未来体感觉皮层的区域表达。cadherin6在早期发病时的功能尚不明确。因此，我们利用全胚培养系统和cadherin6或其显性阴性形式的电穿孔来研究其功能。我们发现，钙粘蛋白6对于早期前脑未来体感觉区域的稳定至关重要。本研究将进一步利用DNA微阵列技术对早期体感区表达的e…More基因进行高通量分析，并利用BAC系统鉴定cadherin6基因的区域特异性表达增强子。其次，遗传上建立的皮层区域通过皮层下区域（即丘脑核）的神经支配进一步分化。我们研究了中心图案的形成机制。几个基因敲除小鼠系表明存在体感觉皮层模式形成的基因。在这个区域，周边晶须图案的表示是地形排列的，称为桶状图。我们利用一种腺病毒载体，携带了对须发育至关重要的小鸡Shh cDNA，研究了外周模式在中心模式形成中的作用。病毒在子宫内感染到胚胎表皮，导致异常的须型。中心图案是外围地图的地形图。结果表明，外围模式是中心模式的最终决定因素。第三，受神经支配的丘脑末梢与皮层第4层神经元形成兴奋性突触。出生后的早期突触只包含NMDA受体，因此在功能上是沉默的。在关键时期（出生后6-7天），沉默突触也转化为含有AMPA受体的活跃突触。我们发现脑源性神经营养因子BDNF在这一激活过程中与NMDA受体介导的神经元活动协同作用是必不可少的。本研究作为AMAP受体的转运机制研究正在进一步发展。少

SUMMARY OF Our research goal wasOur research goal was to understand the molecular basis of functional development of somatosensory cortex. We made three approaches to address this research goal. First, the development of cortical area proceeds through several steps. In the early forebrain, morphogens, like FGF8, Wnt, and Shh are expressed in a gradient according to body axes and induce a series of transcription factors which in turn define the area specific properties of forebrain. One of the area specific genes is cadherin6, which is expressed in the region giving rise to future somatosensory cortex. The function of cadherin6 was uncertain in early areazation. Thus, we studied the function by using whole embryo culture system and electroporation of cadherin6 or a dominant negative form of the molecule. We found that cadherin6 is essential for stabilization of the future somatosensory area in the early forebrain. This study is further developed as a high-through put analysis of genes e … More xpressed in early somatosensory area by DNA microarry as well as identification of enhancers for area specific expression of cadherin6 genes using a BAC system. Second, genetically established cortical areas are further differentiated by innervations from subcortical area, that is, thalamic nuclei. We studied the central pattern formation mechanism. Several knockout mouse lines suggest the existence of genes for pattern formation of somatosensory cortex. In this area, the representation of peripheral whisker patterns are topographically arranged and called as barrel map. We asked the role ofperipheral pattern on the central pattern formation by using an Adenovirus vector harboring chick Shh cDNA which is essential for whisker development. The virus was infected in utero to embryo epidermis, leading to abnormal whisker pattern. The central pattern was the topographic map of the peripheral map. This result showed that the peripheral pattern is the final determinant of the central pattern. Third, the innervated thalamic terminals make excitatory synapses with cortical layer 4 neurons. The early synapses just after birth contains only NMDA receptors, thus are functionally silent. During critical period (6-7days after birth), silent synapses are converted to active synapses containing AMPA receptors too. We found that brain-derived neurotrophic factor, BDNF is essential for this activation process synergistically with neuronal activity mediated by NMDA receptor. This study is further developing as a trafficking mechanism study of AMAP receptors. Less