Specifying the Neocortical Area Map in the Ferret

描述(申请人提供)：我的总体目标是了解新皮质区域图是如何在胚胎和出生后早期哺乳动物的大脑中发展的。在胚胎中如何启动区域图案化的流行模型是基于对大脑平整的小鼠的研究，而支持这一模型的研究旨在揭示哺乳动物的区域图是如何建立的。然而，最近关于轮脑哺乳动物皮质神经元生成的发现表明，将小鼠模型应用于这些物种存在问题。因此，该领域的一个主要担忧是，不可能有新皮质模式的“通用”模型。我建议在这里测试目前的模型是否适用于雪貂回脑皮层的区域地图开发。首先，我将验证雪貂皮质原基(CP)具有与那些模式相似的信号中心 老鼠的大脑皮层。考虑到已经在人类身上发现了一个中心，我预测情况会是这样的。此外，我将确定哪些基因和蛋白质表达模式描绘了出生后小鼠皮质中的区域，也描绘了雪貂的区域边界。在小鼠的端脑中，嘴端纹饰中心(RPC)释放成纤维细胞生长因子(FGF)8，这是一种形态原，以梯度分布在CP上，为皮质祖细胞提供位置值。我预计胚胎雪貂皮质会有一个RPC，它既有皮质结构，也有皮质下结构。宫内微电穿孔(IUME)将用于活体 以控制RPC中FGF8的水平，并在CP中引入新的FGF8来源。这张区域地图将在3周后在幼崽身上进行检查，使用基因和蛋白质表达模式来识别区域边界。如果FGF8控制着雪貂区域图，就像在老鼠身上一样，那么增加嘴FGF8源将使区域边界向尾部移动，扩大吻区，缩小尾区。耗尽来源将产生相反的效果，引入新的FGF8来源将使区域重复。这个项目旨在解决大脑皮层发育领域的一个主要障碍，并(重新)介绍雪貂作为一个物种，在其中研究新皮质区域地图的模式形成机制。充分了解胚胎中人类皮质的发育将有助于理解几种主要的人类神经和精神疾病，这些疾病具有很强的发育成分。

DESCRIPTION (provided by applicant): My overall goal is to understand how the neocortical area map develops in the embryonic and early postnatal mammalian brain. The prevailing model of how area patterning is initiated in the embryo is based on research in the smooth-brained or "lissencephalic" mouse, yet studies that support this model are aimed at revealing how the area map is established in mammals in general. Recent discoveries regarding the generation of cortical neurons in gyrencephalic mammals, however, suggest problems with applying the mouse model to these species. A major concern in the field, therefore, is that there can be no "general" model of neocortical patterning. I propose here to test whether the current model holds for area map development in the gyrencephalic cortex of the ferret. First, I will verify that the ferret cortical primordium (CP) has similar signaling centers to those that pattern the cortex in the mouse. I predict this will be so, given that one center has already been identified in humans. Further, I will identify which of the gene and protein expression patterns that delineate areas in the postnatal mouse cortex also delineate area boundaries in ferret. In the mouse telencephalon, a rostral patterning center (RPC) releases Fibroblast Growth Factor (FGF) 8, a morphogen that disperses in a gradient across the CP supplying positional values to cortical progenitor cells. I expect the embryonic ferret cortex to have an RPC, which patterns both cortical and subcortical structures. In utero microelectroporation (IUME) will be used in live ferret embryos to manipulate levels of FGF8 at the RPC, and to introduce new sources of FGF8 in the CP. The area map will be examined in the pups at 3 weeks, using gene and protein expression patterns to identify area boundaries. If FGF8 controls the ferret area map, as in the mouse, then augmenting the rostral FGF8 source will shift area boundaries caudally, enlarging rostral areas, and shrinking caudal areas. Depleting the source will have opposite effects, and introducing a new source of FGF8 will duplicate areas. This project is designed to address a major stumbling block in the field of cortical development, and to (re)introduce the ferret as a species in which to investigate the mechanisms that pattern the neocortical area map. A full appreciation of human cortical development in the embryo will aid in understanding several major human neurological and psychiatric disorders with a strong developmental component.