Molecular mechanisms regulating mitral cell development

摘要 嗅球(OB)是中枢神经系统(CNS)嗅觉信息的第一个中继站。 OB投射神经元、二尖瓣/簇状细胞、 已经广为人知几十年了，但我们仍然缺乏对它们发展的洞察 机械装置。以往的研究揭示了发育中的二尖瓣细胞的解剖学变化的时间线。 下一步是了解调节特定解剖结构的分子决定因素和途径。 在二尖瓣/簇状细胞发育过程中发生的变化，这是本项目的长期目标。至 为了实现这一目标，我建立了一种新的方法来操纵分子表达的子集 发育中的二尖瓣细胞。使用这种方法，这项提案试图调查几个候选人的角色 二尖瓣细胞发育中的分子。候选分子是三个转录因子(Tbr1，Tbr2， Tbx21)、细胞外基质分子(Reelin)、跨膜蛋白(Protocadherin 21)和 突触囊泡蛋白(VGluT1)。所有这些候选分子之所以被选中，是因为它们 在发育中的OB中，二尖瓣/簇状细胞特异表达。在目标1中，时间表达模式 发育中的二尖瓣细胞的候选分子将被确定。在目标2中，二尖瓣细胞的命运 在没有Tbr1或Tbr2的情况下，将确定前体。在目标3中，我将测试关于 Tbx21、Reelin、Protocadherin 21和vGluT1在形态发育和/或突触中的作用 二尖瓣细胞的形成。这些研究将为我们提供对分子的新的重要见解。 在二尖瓣细胞发育中起作用的决定因素和途径，然后可以作为敲门砖 进一步的研究。我相信这将成为神经回路形成的主要工作之一。 在OB和中枢神经系统其他表达这些分子的地方的发育过程中。

ABSTRACT The olfactory bulb (OB) is the first relay station of olfactory information in the central nervous system (CNS). The general laminar organization and elaborate morphologies of OB projection neurons, mitral/tufted cells, have been well known for several decades, but we continue to lack insight into their developmental mechanisms. Previous studies revealed the timeline of anatomical changes of developing mitral cells. The next step is to understand the molecular determinants and pathways regulating the specific anatomical changes occurring during mitral/tufted cell development, which is the long-term goal of this project. To accomplish this goal, I have established a novel method to manipulate molecular expression in subsets of developing mitral cells. Using this method, this proposal seeks to investigate the roles of several candidate molecules in mitral cell development. The candidate molecules are three transcription factors (Tbr1, Tbr2, Tbx21), an extracellular matrix molecule (Reelin), a transmembrane protein (Protocadherin21), and a synaptic vesicle protein (vGluT1). All of these candidate molecules have been selected because they are specifically expressed by mitral/tufted cells in developing OB. In Aim 1, the temporal expression pattern of candidate molecules in developing mitral cells will be established. In Aim 2, the fate of mitral cell precursors in the absence of Tbr1 or Tbr2 will be determined. In Aim 3, I will test hypotheses regarding the roles of Tbx21, Reelin, Protocadherin21, and vGluT1 in morphological development and/or synapse formation of mitral cells. These studies will provide us with new significant insights into molecular determinants and pathways working in developing mitral cells, which can then serve as a stepping stone to further research. I believe that this will become one of the leading works for neuronal circuitry formation during development of both the OB and elsewhere in the CNS where these molecules are expressed.