The roles of non-coding and protein-coding genes in the evolutionary expansion of the cerebral cortex

脑组织的多样性在脊椎动物中是壮观的。最大的变异出现在背侧皮质及其与其他结构交界处附近(在大脑皮质/大脑皮质下交界处)。鸟类和爬行动物大脑的背侧皮质只包含哺乳动物六层等皮质的一部分。虽然所有哺乳动物的等皮质的基本结构都是相似的，但哺乳动物的皮质大小和复杂性急剧增加，最终达到人脑的水平。比较发育研究表明，有丝分裂间隔的细化可能是哺乳动物皮质进化的驱动因素(Rakic，1995；2006；Kriegstein等人，2006；Molnar等人，2006a，b)。通过研究各种不同物种的皮质发育，可以了解导致这些变异的机制和基因。这项建议研究了两组基因。(1)第一组由蛋白质编码基因组成，已知参与皮质神经发生、层的形成、神经元的径向和切向迁移。(2)第二类包括非编码的所谓‘大RNA’基因，它们表现出明显的净化选择特征，暗示着功能。利用现代遗传学和比较基因组学的工具，我们将对这两类基因进行测序和比较，并在基因敲除小鼠以及体外和体内实验范式中测试它们的功能。通过对这些编码和非编码基因的研究，我们希望在不同的分类群中确定最常见的皮质发育基因的作用背景。大脑皮层发育的比较方面不仅指向进化上的相关变化，而且也让我们注意到目前用于理解人类大脑皮层发育异常的一些模型系统的局限性，并确实揭示了导致这些异常的机制。

The diversity of brain organizations is spectacular amongst vertebrates. The greatest variations are observed in the dorsal cortex and near its junction to other structures (at the pallial/subpallial boundary). Dorsal cortex of avian and reptilian brains contains only a component of the six layered isocortex of mammals. Although fundamental structures of the isocortex are similar in all mammals, there is a drastic increase in cortical size and complexity in mammals culminating with the human brain. Comparative developmental studies suggest that the elaboration of the mitotic compartments might have been the drive behind mammalian cortical evolution (Rakic, 1995; 2006; Kriegstein et al., 2006; Molnar et al., 2006a,b). The mechanisms and genes responsible for generating these variations can be understood by studying cortical development in various different species. This proposal examines two groups of genes. (1) The first group consists of protein coding genes which are known to be involved in cortical neurogenesis, formation of layers, radial and tangential migration of neurons. (2) The second assortment includes non-coding so-called 'macro-RNA' genes that exhibit distinct signatures of purifying selection, suggestive of functionality. Using the tools of modern genetics and comparative genomics we shall sequence and compare selected groups of genes from both categories and test their function in knockout mice and in in vitro and in vivo experimental paradigms. Through the study of these coding and non-coding genes, we wish to determine, in various taxa, the context in which the most common cortical development genes operate. Comparative aspects of cortical development not only point to evolutionarily relevant changes, but they also draw our attention to the limitations of some of the model systems currently used to understand human cortical developmental abnormalities and indeed reveal the mechanisms responsible for these abnormalities.