Origin of Cortical Species-specific Distinctions

描述（由申请人提供）：人类皮质与其他物种的区别在于其大小、增加的专门细胞结构区域、新的神经元亚型和增加的连接数量，这些连接有助于独特的功能，如语言和高阶认知。人类皮层区别在发育过程中出现的机制以及它在进化过程中是如何进化的尚不清楚。皮质中的进化新奇性可能是影响早期胚胎阶段基因表达的时间、序列和水平的相对较小的遗传差异的结果，这只能通过研究人类和非人类灵长类动物与啮齿动物和其他物种相比的皮质形成的独特特征来揭示。基因，转录因子和细胞机制，产生种属特异性差异和人类的区别在皮层发育以前没有被分析，我们是在独特的位置，以解决这个生物医学上的重要性，但在现代神经科学被忽视的问题。人类端脑原基可以从其大小，形态，神经干细胞类型，和迄今尚未认识到的abventricular干细胞从局部增殖脑室区神经发生的发病前两周从小鼠和猴的区别。因此，我们将专注于在啮齿类动物（小鼠），非人灵长类动物（猕猴）和人类端脑皮质发育的初始阶段，通过使用最先进的遗传分子和体外和体内细胞生物学方法。具体而言，我们将进行：1）这三个物种的早期脑室、脑室下和脑室外神经干细胞的分离、体内谱系分析和组织化学表征、命运确定以及功能和潜力的测试; 2）在人类中差异调节的基因的鉴定，利用高通量微阵列基因表达分析和原位杂交分析研究猕猴和小鼠的早期干细胞类型;和，3）在特定目标1和2中筛选的基因的功能研究。人类大脑皮层的异常发生和初始模式可以引起独特的人类神经精神障碍，例如精神分裂症、自闭症、发育性阅读障碍、智力迟钝和对治疗药物的反应和滥用。公共卫生相关性：拟议的研究重点是细胞和分子事件的初始步骤，这些事件建立了人类胚胎，非人类灵长类动物和啮齿动物大脑皮层之间的解剖和功能差异。关于物种特异性差异的起源和性质的预期独特数据集不仅具有理论意义，而且具有相当大的临床意义，因为许多新进化的特征可能更容易受到遗传和环境因素的影响，这些因素可能引发某些人类特有的神经精神疾病，如精神分裂症、自闭症、发育性阅读障碍、智力迟钝以及对治疗和滥用药物的反应。

DESCRIPTION (provided by applicant): The human cortex is distinguished from other species by its size, addition of specialized cytoarchitectonic areas, new subtypes of neurons and increased number of connections that subserve unique functions such as language and higher order cognition. The mechanism by which human cortical distinction emerges during development and how it has evolved during evolution is not known. The evolutionary novelties in the cortex are likely to be an outcome of relatively small genetic differences effecting the timing, sequence and level of gene expression at early embryonic stages that can be uncovered only by studying unique features of cortical formation in human and non-human primates in comparison to rodent and other species. Genes, transcription factors and cellular mechanisms that generate species-specific differences and human distinction in cortical development have not been previously analyzed and we are in the unique position to address this biomedically significant, but neglected issue in modern neuroscience. The human telencephalic primordium can be distinguished from that of the mouse and monkey by its size, morphology, neural stem cell types, and hitherto unrecognized abventricular stem cells two weeks before the onset of neurogenesis from the local proliferative ventricular zone. Thus, we will focus on the initial stages of cortical development in the rodent (mouse), non-human primate (macaque) and human telencephalon by using the most advanced genetic molecular and in vitro and in vivo cell biological methods available. More specifically, we will perform: 1) Isolation, in vivo lineage analysis and histochemical characterization, fate determination and testing function and potential of the early ventricular, subventricular and abventricular neuronal stem cells in these three species; 2) Identification of genes differentially regulated among human, macaque and mouse early stem cell types using high throughput microarray gene expression analysis and in situ hybridization analysis of putatively differentially regulated genes; and, 3) Functional studies of genes screened in Specific Aim 1 & 2. Abnormal genesis and initial patterning of the human cerebral cortex can give rise to uniquely human neuropsychiatric disorders such as schizophrenia, autism, developmental dyslexia, mental retardation and response to drugs for therapy and abuse. PUBLIC HEALTH RELEVANCE: The proposed research focuses on the initial steps of cellular and molecular events that establish anatomical and functional differences between the embryonic human, non-human primates and rodent cerebral cortex. The expected set of unique data on the origin and nature of species-specific differences are not only of theoretical, but also of considerable clinical significance, as many of the newly evolved traits may be more vulnerable to genetic and environmental factors that can initiate certain human-specific neuropsychiatric disorders such as schizophrenia, autism, developmental dyslexia, mental retardation and response to drugs used in therapy and abuse.