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， 以及多种细胞谱系的分化。连续的发展计划控制着 单个神经元类型的确定和增殖、细胞迁移、轴突延伸，以及最终的神经元分化。 功能性突触连接的形成。这些步骤中的大多数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。遗传 成熟神经元从它们的祖细胞分化的程序在很大程度上仍然是未知的， 然而，部分原因是在天然环境中研究神经干细胞的困难。 在脊椎动物的嗅觉系统中，初级感觉神经元在整个成年过程中不断再生 通过神经祖细胞的增殖和分化来维持生命。这一特点使得嗅觉系统 特别适合于神经干细胞特性的研究。虽然这个谱系的某些阶段 已经用一组有限的分子标记进行了鉴定，这些分子标记是基因程序， 调节嗅觉神经发生的机制在很大程度上仍是未知的。这个生物学中固有的巨大复杂性， _problem要求.qene表达式的. qnView视图，以便充分理解，qenetic网络 这个发育系统中的神经功能和发育。 在这个应用程序中，我们提出了一套基于DNA微阵列的技术来识别-在一个，qq规模- qene的表达模式与嗅觉神经元线的不同阶段相对应，qe。我们建议（1） 在胚胎发育过程中对嗅上皮中的基因表达进行时间分析， 损伤诱导的再生，以确定与不同的基因相关的基因和基因表达程序， 该谱系的阶段，包括最早的多能祖细胞阶段;以及（2）通过以下方法来完善该分析： 比较已知破坏嗅觉神经发生的突变体的基因表达模式，并验证 通过RNA原位杂交进行基于微阵列的预测。 我们的方法有望产生有关分子和途径的高度详细的信息 嗅觉感觉神经元从其祖细胞的发生。此外，一个更广泛的小组 将产生嗅觉神经发生的不同阶段的分子标记。对这些问题的解释 qenetic pro，qram在qenome范围的水平将提供有价值的insi.qhts到pro，qenitor的属性 来自各种神经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.