Diversification and Function of Spinal V2b-Derived Neurons

描述（由申请人提供）：本研究将与Guillermo Lanuza博士合作在阿根廷进行，作为NIH/NINDS资助5 R37 NS 037075 -09的扩展。抑制性脊髓中间神经元的功能分析（8/15/2006-3/31/2010）。最近在脊髓发育中的研究已经导致了一种模型，在该模型中，神经元最初由独特的遗传程序决定，该遗传程序由在背腹侧限制的前体群体中表达的转录因子的组合作用控制。尽管在理解细胞命运规范的早期事件方面取得了相当大的进展，但导致成人中成熟神经元细胞类型的规范和生成的机制仍有待阐明。在这项研究中，我们将解决至少两个不同的子集的脊髓和脑干的胚胎V2 B中间神经元的多样化：a）抑制性神经元，延长轴突同侧和B）神经元，接触脑脊液（CSF）在中央管。我们将研究接触CSF的神经元的发育，并询问它们是否构成晚出生的V2 b神经元群体。我们将通过关注转录因子Foxn 4和Mash 1在V2 b前体中发挥的作用来定义指定通用V2 b或V2 b亚型身份的遗传程序。此外，我们将测试我们的假设，即Gata 2和Gata 3控制CFS-contacting神经元的分化。最后，我们将确定在体内的中央管神经元的功能。它们作为化学传感器和调节器的内部流体的稳态的作用将在实验中使用基因消融方法来探测它们的功能进行评估。公共卫生相关性：这些研究将使我们更好地理解脊髓和脑干神经元多样化的机制。更重要的是，它们将为治疗脊髓损伤、退行性疾病和呼吸功能障碍的策略奠定基础。

DESCRIPTION (provided by applicant): This research will be done in Argentina in collaboration with Dr. Guillermo Lanuza as an extension of the NIH/NINDS grant 5 R37 NS037075-09. Functional Analysis of Inhibitory Spinal Cord Interneurons (8/15/2006-3/31/2010). Recent studies in the developing spinal cord have led to a model in which neurons are initially determined by unique genetic programs controlled by the combinatorial action of transcription factors expressed in dorsoventrally restricted populations of precursors. In spite of the considerable progress made in understanding early events in cell fate specification, the mechanisms that lead to the specification and generation of mature neuronal cell types in the adult remain to be elucidated. In this research proposal we will address the diversification of embryonic V2b interneurons of the spinal cord and brainstem in at least two different subsets: a) inhibitory neurons that extend axons ipsilaterally and b) neurons that contact the cerebrospinal fluid (CSF) in the central canal. We will study the development of CSF- contacting neurons and ask whether they constitute a late-born population of V2b neurons. We will define the genetic program that specifies generic V2b or V2b subtype identity by focusing on the role that the transcription factors Foxn4 and Mash1 play in V2b precursors. In addition we will test our hypothesis that Gata2 and Gata3 control the differentiation of CFS-contacting neurons. Finally, we will determine the function in vivo of central canal neurons. Their role as chemosensors and regulators of homeostasis of the internal fluid will be assessed in experiments using genetic ablation approaches to probe their function. PUBLIC HEALTH RELEVANCE: These studies will yield a better understanding of the mechanisms that underlie neuronal diversification in the spinal cord and the brainstem. More importantly, they will lay the groundwork for strategies to treat spinal cord injury, degenerative disorders and respiratory dysfunctions.