PROGRAMS OF GENE EXPRESSION IN OLFACTORY NEUROGENESIS

神经系统中神经元多样性的产生是一个复杂的过程，涉及到规范 以及多种细胞谱系的分化。连续的发育计划控制着 单个神经元类型、细胞迁移、轴突延伸以及最终 功能性突触连接的形成。这些步骤中的大多数都是由特定的基因表达控制的 程序，例如导致神经元前体产生的细胞命运决定。基因 成熟神经元与其祖细胞分化的程序在很大程度上仍不为人所知， 然而，部分原因是在其自然环境中研究神经干细胞的难度。 在脊椎动物的嗅觉系统中，初级感觉神经元在成年后不断再生。 通过神经前体细胞的增殖和分化来维持生命。这一特征使嗅觉系统 尤其适合研究神经干细胞的特性。虽然这一血统的某些阶段 都是通过一组有限的分子标记来鉴定的，这些遗传程序既定义了 对嗅觉神经发生的调控在很大程度上仍是未知的。这种生物所固有的巨大复杂性， _roblem需要.qene表达式的.qglobal视图才能完全理解qenetic网络 Jnderlyin.q神经在这个发育系统中的功能和发育。 在本申请中，我们提出了一套基于DNA微阵列的技术，以在全球范围内识别 Qene的表达模式与嗅神经元线Qe的不同阶段相对应。我们建议(1) 对胚胎发育过程中嗅觉上皮基因表达进行时间谱分析 病损诱导再生鉴定相关基因和基因表达程序的差异 这一谱系的各个阶段，包括最早的多能祖细胞阶段；以及(2)通过以下方式改进这一分析 比较已知可扰乱嗅神经发生的突变体的基因表达模式，并验证 基于微阵列的RNA原位杂交预测。 我们的方法有望得到有关分子和通路的非常详细的信息。 嗅觉感觉神经元由其祖细胞发育而来。此外，更广泛的小组成员 将为嗅觉神经发生的不同阶段产生分子标记。对这些问题的解释 ，qenetic PRO，QRAMs在全基因组水平上将为了解PRO，Qenitor的性质提供有价值的信息 来自各种神经系统和非神经系统的干细胞。

The generation of neuronal diversity in the nervous system is a complex process involving the specification and differentiation of a multitude of cellular lineages. Successive developmental programs control the determination and proliferation of individual neuronal types, cell migration, axon extension, and ultimately the formation of functional synaptic connections. Most of these steps are controlled by specific gene expression programs, such as cell fate decisions that lead to the generation of neuronal precursors. The genetic programs underlying the differentiation of mature neurons from their progenitors remain largely unknown, however, in part because of the difficulty in studying neuronal stem cells in their native environments. In the vertebrate olfactory system, primary sensory neurons are continuously regenerated throughout adult life via the proliferation and differentiation of neural progenitor cells. This feature makes the olfactory system particularly amenable for studies on the properties of neuronal stem cells. While some stages of this lineage have been identified with a limited set of molecular markers, the genetic programs that both define and regulate olfactory neurogenesis remain largely unknown. The enormous complexity inherent in this biolo,qical _roblem demands a .qlobal view of .qene expression in order to fully understand the ,qenetic networks Jnderlyin.q neural function and development in this developmental system. In this application we propose a suite of DNA microarray-based techniques to identify - on a ,qlobal scale - patterns of .qene expression correspondin.q to distinct sta.qes of the olfactory neuron linea,qe. We propose (1) to perform temporal profiling of gene expression in olfactory epithelium during embryonic development and lesion-induced regeneration to identify the genes and gene expression programs associated with distinct stages of this lineage, including the earliest multipotent progenitor stage; and (2) to refine this analysis by comparing gene expression patterns in mutants known to disrupt olfactory neurogenesis, and to validate the microarray-based predictions by RNA in situ hybridizations. Our approach is expected to yield highly detailed information about the molecules and pathways responsible for the genesis of olfactory sensory neurons from their progenitor cells. In addition, a broader panel of molecular markers will be generated for distinct stages of olfactory neurogenesis. The elucidation of these ,qenetic pro,qrams at the ,qenome-wide level will provide valuable insi.qhts into the properties of pro,qenitor stem cells from a variety of neural and non-neural systems.