Molecular mechanisms regulating mitral cell development

描述（由申请人提供）：嗅球（OB）是中枢神经系统（CNS）中嗅觉信息的第一个中继站。二尖瓣/簇状细胞是OB投射神经元的一般层状组织和复杂的形态，几十年来一直为人所知，但我们仍然缺乏对其发育机制的了解。以往的研究揭示了二尖瓣细胞发育的解剖变化时间。下一步是了解二尖瓣/簇状细胞发育过程中调节特定解剖变化的分子决定因素和途径，这是本项目的长期目标。为了实现这一目标，我建立了一种新的方法来操纵发育中的二尖瓣细胞亚群中的分子表达。利用这种方法，本研究旨在研究几种候选分子在二尖瓣细胞发育中的作用。候选分子是三个转录因子（Tbr1, Tbr2, Tbx21），一个细胞外基质分子（Reelin），一个跨膜蛋白（Protocadherin21）和一个突触囊泡蛋白（vGluT1）。所有这些候选分子都被选中，因为它们在发育中的二尖瓣/簇状细胞中特异性表达。在Aim 1中，候选分子在发育中的二尖瓣细胞中的时间表达模式将被建立。在Aim 2中，二尖瓣细胞前体在缺乏Tbr1或Tbr2的情况下的命运将被确定。在Aim 3中，我将测试关于Tbx21、Reelin、Protocadherin21和vGluT1在二尖瓣细胞形态发育和/或突触形成中的作用的假设。这些研究将为我们了解二尖瓣细胞发育过程中的分子决定因素和途径提供新的重要见解，从而为进一步的研究奠定基础。我相信这将成为在OB和CNS中其他地方这些分子表达的发育过程中神经回路形成的主要工作之一。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Olfactory information is transmitted to diverse brain regions through mitral/tufted cells in the olfactory bulb. Several developmental disorders also have olfactory dysfunctions: for example, many Asperger's syndrome children have hyperosima (increased ability to smell) or hyposmia (reduced ability to smell); and Kallmann syndrome patients have anosmia (inability to smell). The general goal of this project is to understand the developmental mechanisms of mitral/tufted cells which could help in finding a cure of these olfactory dysfunctions.