Origin of Cortical Species-specific Distinctions

描述（由申请人提供）：人类皮层与其他物种的区别在于它的大小，增加了专门的细胞结构区域，新的神经元亚型和增加的连接数量，这些连接服务于语言和高阶认知等独特功能。人类皮层区分在发育过程中产生的机制以及在进化过程中如何进化尚不清楚。大脑皮层的进化新颖性可能是相对较小的基因差异的结果，这些基因差异影响了胚胎早期阶段基因表达的时间、序列和水平，只有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大脑皮层形成的独特特征，才能发现这些差异。基因、转录因子和细胞机制在皮层发育过程中产生物种特异性差异和人类差异，这在以前没有被分析过，我们处于独特的位置，可以解决这个在现代神经科学中具有重要生物医学意义但却被忽视的问题。人类远端脑原基的大小、形态、神经干细胞类型，以及在局部增殖性脑室区发生神经发生前两周尚未被识别的腹侧干细胞，可以与小鼠和猴子的脑原基区分开来。因此，我们将重点研究啮齿动物（小鼠）、非人类灵长类动物（猕猴）和人类端脑皮层发育的初始阶段，使用最先进的遗传分子和体外和体内细胞生物学方法。更具体地说，我们将进行：1)这三个物种的早期脑室、脑室下和脑室下神经元干细胞的分离、体内谱系分析和组织化学表征、命运确定和测试功能和潜力；2)利用高通量微阵列基因表达分析和原位杂交分析推测的差异调控基因，鉴定人、猕猴和小鼠早期干细胞类型的差异调控基因；3)特异性Aim 1和2中筛选基因的功能研究。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疾病，如精神分裂症、自闭症、发育性阅读障碍、智力迟钝和对药物治疗和滥用的反应。公共卫生相关性：拟议的研究侧重于在胚胎人类、非人类灵长类动物和啮齿动物大脑皮层之间建立解剖和功能差异的细胞和分子事件的初始步骤。关于物种特异性差异的起源和本质的预期的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异性神经精神疾病，如精神分裂症、自闭症、发育性阅读障碍、智力迟钝和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.