Molecular Genetics of Sensory Organ Development

描述（由申请人提供）：本项目的长期目标是详细了解发育中动物外胚层中神经细胞命运的具体情况。在所有已研究的物种中，这一过程取决于“原神经”基因的活性，这些基因编码一个独特的碱性螺旋-环-螺旋转录激活蛋白家族。我们最近在果蝇的初步研究已经揭示了存在的新模式的调节的前神经基因（转录和转录后），并已确定了一组非常有趣的基因，在成人外周神经系统（PNS）的发展过程中的前神经下游表达。该项目有三个主要目标，都集中在前神经基因活性的调节和功能： (1)探讨前神经基因与Notch介导的侧抑制的功能关系。 (2)研究前神经基因活性转录后调控的新模式。 (3)研究前神经基因下游基因的功能和调控。我们认为，果蝇成体PNS（近世纪前，在那里首次从遗传学上揭示了前神经基因的存在）仍然是研究这些关键细胞命运决定因素的一个特别有利的场所。尽管如此，该项目的结果可能会有意义远远超出了特定的设置飞PNS。特别重要的是观察到具有“神经内分泌”表型的广谱人类肿瘤与原神经基因的强烈过表达相关，包括小细胞肺癌（最致命的肺癌形式）和神经母细胞瘤（侵袭性儿童癌症）。通过阐明通常负调节前神经基因活性的转录和转录后机制，我们的工作可能为这些疾病的发病机制提供重要的见解。通过帮助阐明神经发生的共同机制，我们还希望为我们对动物如何构建神经系统的广泛理解做出实质性贡献。

DESCRIPTION (provided by applicant): The long-term goal of this project is a detailed understanding of how neural cell fates are specified in the ectoderm of developing animals. In all species that have been studied, this process depends on the activity of "proneural" genes, which encode a distinctive family of basic helix-loop-helix transcriptional activator proteins. Our recent preliminary studies in Drosophila have revealed the existence of novel modes of regulation of the proneural genes (both transcriptional and post-transcriptional), and have defined a set of very interesting genes that are expressed downstream of the proneurals during adult peripheral nervous system (PNS) development. This project has three major objectives, all focused on the regulation and function of proneural gene activity: (1) Investigate the functional relationship between proneural genes and Notch-mediated lateral inhibition. (2) Investigate novel modes of post-transcriptional regulation of proneural gene activity. (3) Investigate the function and regulation of genes that act downstream of proneural genes. The Drosophila adult PNS (where the existence of the proneural genes was first revealed genetically-nearly a century ago) remains, we think, a particularly advantageous venue in which to study these key cell fate determinants. Nevertheless, the results of this project may be expected to have significance well beyond the particular setting of the fly PNS. Of particular importance is the observation that a broad spectrum of human tumors with a "neuroendocrine" phenotype are associated with strong overexpression of proneural genes, including small cell lung cancer (the most lethal form of lung cancer) and neuroblastoma (an aggressive childhood cancer). By elucidating both transcriptional and post-transcriptional mechanisms that normally regulate proneural gene activity negatively, our work may offer important insight into the pathogenesis of these diseases. By helping to illuminate shared mechanisms of neurogenesis, we also expect to contribute substantially to our broad understanding of how animals build their nervous systems.