PROGRAMS OF GENE EXPRESSION IN OLFACTORY NEUROGENESIS

描述（由申请人提供）：神经系统中神经元多样性的产生是一个复杂的过程，涉及大量细胞谱系的规范和分化。连续的发育程序控制着单个神经元类型的决定和增殖、细胞迁移、轴突延伸，并最终形成功能性突触连接。这些步骤中的大多数是由特定的基因表达程序控制的，例如导致神经元前体产生的细胞命运决定。然而，成熟神经元从其祖细胞分化的遗传程序在很大程度上仍然未知，部分原因是难以在其原生环境中研究神经干细胞。

DESCRIPTION (provided by applicant): 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 biological problem demands a global view of gene expression in order to fully understand the genetic networks underlying neural function and development in this developmental system. In this application we propose a suite of DNA microarray-based techniques to identify - on a global scale - patterns of gene expression corresponding to distinct stages of the olfactory neuron lineage. 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 programs at the genome-wide level will provide valuable insights into the properties of progenitor stem cells from a variety of neural and non-neural systems.