Developmental Mechanisms of Neurogenesis

我们对神经系统胚胎发育的了解大多来自于对苍蝇或老鼠的研究。由于这些研究揭示了类似的信号系统和分子途径，因此有人提出，神经系统在多细胞动物的早期历史中只出现过一次。随后对几种无脊椎动物的研究支持了这一观点，但神经系统发育方式的惊人多样性使得很难将单一起源合理化。一种更精确的解释是，在许多群体中存在着细胞组织的独立进化，随着动物的多样化，神经发生以各种方式利用了保守的信号系统和分子途径。我们缺乏必要的模型来验证这一假设，因为神经发生的分子和细胞机制需要仔细分析，以便在相关动物群体中进行有用的比较。**后口动物是一大群动物，包括脊椎动物和一些无脊椎动物，它们通过分子亲缘关系的测量密切相关，但体型却非常不同。后口动物神经系统的组织从简单到非常复杂。为了更好地了解多细胞动物的起源和多样化，我制定了一项研究计划，其长期目标是确定海胆胚胎中神经发生的细胞和分子机制。这些研究将建立一个新的神经发生模型，并为后生动物的进化提供新的见解。海胆是棘皮动物，是后口动物的基础类群之一，因此它们在神经发生中的机制揭示了所有后口动物共有的基本特征，以及那些在更复杂的后口动物中出现的特征。150年来，海胆一直被用来研究早期发育的许多方面。优良的基因组资源，控制基因表达的简单系统，以及清晰的胚胎，有利于成像，使海胆成为优秀的模型。拟议的研究将检查专用的神经祖细胞，或神经干细胞。它将确定Notch信号和成纤维细胞生长因子（FGF）信号在神经发生中的作用。此外，它将确定中枢神经系统是否有模式，或表达某些转录因子，并在特定的解剖位置有专门的神经祖细胞。该研究将使用新颖的方法，并将产生独特的试剂来进一步使用该模型。建议的研究是优秀的项目，学生的培训提供了高度所需的技能，确保他们进一步的成功。这项研究将在各个学科中产生广泛的影响，因为了解胚胎细胞转化为复杂神经系统的细胞和分子机制与发育生物学、神经生物学、进化生物学、细胞生物学和分子生物学有关。＊＊＊＊

Most of what we know about the embryonic development of nervous systems comes from studies of flies or mice. As those studies revealed similar signaling systems and molecular pathways, it was proposed that nervous systems arose once, early in the history of multicellular animals. Subsequent studies in several types of invertebrates support this idea, but the striking diversity in how nervous systems develop makes it difficult to rationalize a single origin. A more refined explanation is that there has been independent evolution of the cellular organization in many groups and neurogenesis has drawn upon conserved signaling systems and molecular pathways in various ways as animals diversified. We lack the models necessary to test this hypothesis, as the molecular and cellular mechanisms underlying neurogenesis need to be carefully analyzed to make useful comparisons in groups of related animals. ** Deuterostomes are a large grouping of animals including vertebrates and several invertebrates groups that are closely related by measurements of molecular kinship, yet have very diverse body forms. The organization of nervous systems within the deuterostomes ranges from simple to very complex. To better understand the origin and diversification of multicellular animals I have developed a research program with the long-term objective of determining the cellular and molecular mechanisms of neurogenesis in sea urchin embryos. These studies will establish a novel neurogenesis model and provide new insights into metazoan evolution. Sea urchins are echinoderms, one of the basal groups of deuterostomes, so mechanisms they employ in neurogenesis reveal fundamental features shared by all deuterostomes, and those that have arisen in more complex deuterostomes. Sea urchins have been used for 150 years to study many aspects of early development. Excellent genomic resources, simple systems for controlling gene expression, and clear embryos, conducive to imaging, make sea urchins excellent models. The proposed studies will examine dedicated neural progenitors, or neural stem cells. It will determine how Notch signaling and fibroblast growth factor (FGF) signaling function in neurogenesis. As well, it will determine if the central nervous system is patterned, or expresses certain transcription factors and has dedicated neural progenitors in specific anatomical locations. The research will use novel methods and will generate unique reagents to further use of this model. The proposed studies are excellent projects for students, and the training gives highly desired skills that ensure their further success. This research will have broad impact across disciplines, because understanding the cellular and molecular mechanisms by which embryonic cells are transformed into a complex nervous system is relevant to developmental biology, neurobiology, evolutionary biology, cell, and molecular biology. ****