探索灵长类动物丘脑释放的皮层分化因子

In mammalian evolution, primates acquired a highly developed cerebral cortex. However, the molecular basis of this evolutionary advancement in cortical expansion is largely unknown. Previously, we revealed heterogeneous gene expression between the striate cortex (V1) and association areas in adult monkeys. As this differential pattern was not observed in non-primate mammalian species, it suggested a possible role of these genes in cortical evolution. In this proposal, we aim to elucidate what regulates the heterogeneity of cortical gene expression in primates. The expression pattern of V1-selective genes was significantly correlated with geniculo-cortical afferent distribution; therefore, we hypothesize that the thalamo-cortical synaptic contacts and/or secretion of certain signaling molecule(s) from thalamo-cortical afferent may induce expression of a group of genes in cortical neurons. To identify the thalamus-derived cortical differentiation factor of primates, we propose to compare transcriptomes of the dorsal lateral geniculate nucleus (dLGN) and V1 in macaques and rats. First, we will make a list of genes that are preferentially expressed in the dLGN in the macaque. Second, we do the same analysis in the rat, and subtract the rat list from the macaque list to identify a group of dLGN-selective genes exclusively in the macaque. By examining their mRNA and protein expression patterns and correlating with available database of protein types, we will narrow down from whole-genome to less than 5 candidate genes. We propose to conduct loss-of-function and gain-of-function experiments to determine their impact on inducing V1-selective genes in cortical neurons. We further propose to investigate function of those genes on generating cell morphology and physiology characteristic to primate V1. This knowledge gained from these studies will form the basis of a molecular foundation of primate cortical development and evolution and impact our understanding of congenital cortical malformations in humans.

灵长类动物有高度分化的大脑皮层，但这种进化优势的分子机制尚不明确。此前，我们曾发现成年猴视皮层和联络区的基因表达差异。但在非灵长类哺乳动物中并未观察到这种差异，表明这些基因可能在皮层进化中起到一定作用。在本课题中，我们打算研究是什么调控着灵长类动物的这种基因差异性表达。我们假设丘脑-皮层传入末梢分泌特定的信号因子可引起一些皮层神经元基因的表达。首先，我们对猕猴的外侧膝状体和视皮层进行全基因组的转录组比较，得到在猕猴外侧膝状体高表达的基因列表。然后我们对大鼠进行相同操作，用所得到的猕猴基因列表减去大鼠列表，筛选出仅在猕猴外侧膝状体中高表达的基因，我们会最终锁定不超过5个基因，并进行功能丧失和功能获得实验，来确定它们是否能促进皮层神经元视皮层选择性基因的表达。我们还打算研究这些基因对于表现型的影响。这个研究有望解释灵长类动物皮层发育和进化的分子基础，并且明确人类大脑发育畸形的基因基础。

在哺乳动物的进化中，灵长类动物进化出高度发达的大脑皮层，并发育出高度规则、可处理信息的皮层柱结构，但其分子机制尚不明确。申请者曾研究出成年猴纹状皮层（V1）和联络区的基因表达差异，而在非灵长类哺乳动物中并未观察到这种差异，表示这些基因可能在皮层进化中起到一定作用。本课题旨在阐明调控灵长类动物中基因差异性表达及皮层功能柱发育的机制。本课题假设丘脑-皮层间的突触连接，或者丘脑-皮层传入末梢分泌的特定信号因子可引起一些皮层神经元基因的表达。为了研究灵长类动物丘脑释放出的皮层分化因子，申请者对猕猴和大鼠的背外侧膝状体（dLGN）和V1进行全基因组的转录组对比，筛选出一种在灵长类动物丘脑中特异性表达的基因：NPTX2。NPTX2的表达依赖于神经活动，该蛋白转运到轴突末梢后，由突触前膜分泌到后膜，增强突触传递效率。申请者认为丘脑产生的NPTX2通过增强Hebbian可塑性来促进皮层柱边界的形成，并在大鼠外侧膝状体进行了NPTX2过表达实验，且拟在狨猴外侧膝状体进行基因下调实验，检测初级视皮层的眼优势柱是否形成或发育异常，以阐明NPTX2对大鼠和狨猴皮层柱发育的影响。本研究将阐明灵长类动物大脑皮层发育和进化的分子基础，帮助理解人类先天性皮层畸形的机制。

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