Regional Control of Telencephalic Neuronal Diversity

端脑神经元多样性的区域控制

• 批准号: 6870780
• 负责人: KENNETH J CAMPBELL
• 金额: $ 32.42万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870780
• 关键词: cell population study; corpus striatum; developmental genetics; developmental neurobiology; embryo /fetus; fluorescence microscopy; gene mutation; genetic mapping; genetically modified animals; histology; homeobox genes; interneurons; laboratory mouse; nerve stem cell; neurogenesis; neurogenetics; neuronal guidance; newborn animals; olfactory lobe; telencephalon; terminal nick end labeling; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): The mature CNS is comprised of a multitude of different neuronal subtypes. This diversity in neuronal subtypes is fundamental to the many complex functions that the CNS controls. The generation of neuronal diversity in the developing CNS seems to be controlled by localized production of neuronal subtypes and the subsequent distribution of these subtypes within the brain via migration. Localized neuronal generation is dependent on the formation and output of discrete neuronal progenitor domains. This proposal will focus on two such progenitor domains in the lateral ganglionic eminence (LGE) of the telencephalon. This region of the developing brain gives rise to the projection neurons of the striatum as well as interneurons in the olfactory bulb. Gene expression studies have suggested that the LGE can be divided into a dorsal (dLGE) and ventral (vLGE) domain. The dLGE expresses the ETS transcription factor gene Er81 while the vLGE is marked by the LIM homeobox gene Islet1 (Isl1). We have recently identified a new marker of the dLGE called Sp8, which is a new member of the Sp1 transcription factor family. Our previous work led us to propose that the dLGE and vLGE give rise to distinct neuronal progeny, namely the olfactory bulb intemeurons and striatal projection neurons, respectively. The main goal of this proposal is to test this hypothesis by the experiments outlined in the following 3 specific aims. Specific aim 1 will use genetic fate mapping to follow the neurons derived from either the Isl1-expressing-vLGE or the Sp8-expressing dLGE. Specific Aim 2 will determine the role of Sp8 in dLGE and olfactory bulb interneuron development using conditional mutagenesis and over-expression. Finally, Specific Aim 3 will examine the requirement of Isl1 for vLGE development using conditional mutagenesis and over-expression both in vivo and in vitro. Many neuro-psychiatric disorders such as attention deficit hyperactivity disorder (ADHD), Tourette's syndrome and Schizophrenia, which affect children and young adults, are thought to result, at least in part, from abnormal striatal function. Recent thinking supports the idea that these brain disorders may be due, at least in part, to abnormalities of brain development. Thus knowledge of the mechanisms that regulate neuronal diversity in the LGE is likely to contribute to a better understanding and possibly treatments of these brain disorders.

描述（由申请人提供）：成熟CNS由多种不同的神经元亚型组成。神经元亚型的这种多样性是CNS控制的许多复杂功能的基础。在发育中的CNS中神经元多样性的产生似乎是由神经元亚型的局部产生和这些亚型随后通过迁移在脑内的分布控制的。局部神经元的产生依赖于离散神经元祖域的形成和输出。这项建议将集中在两个这样的祖域在端脑的外侧神经节隆起（LGE）。发育中的大脑的这个区域产生纹状体的投射神经元以及嗅球中的中间神经元。基因表达研究表明，LGE可分为背侧（dLGE）和腹侧（vLGE）结构域。dLGE表达ETS转录因子基因Er81，而vLGE由LIM同源框基因Islet 1（Isl1）标记。我们最近发现了一个新的dLGE标记物Sp8，它是Sp1转录因子家族的新成员。我们以前的工作使我们提出，dLGE和vLGE产生不同的神经元后代，即嗅球中间神经元和纹状体投射神经元，分别。本提案的主要目标是通过以下3个具体目标中概述的实验来验证这一假设。具体目标1将使用遗传命运作图来追踪源自表达Isl1的vLGE或表达Sp8的dLGE的神经元。具体目标2将使用条件诱变和过表达确定Sp8在dLGE和嗅球中间神经元发育中的作用。最后，具体目标3将使用条件诱变和体内和体外过表达来检查Isl1对vLGE开发的需求。许多影响儿童和年轻人的神经精神障碍，如注意力缺陷多动障碍（ADHD）、图雷特综合征和精神分裂症，被认为至少部分是由异常的纹状体功能引起的。最近的想法支持这样一种观点，即这些大脑疾病可能是由于，至少部分是由于大脑发育异常。因此，了解LGE中调节神经元多样性的机制可能有助于更好地理解和治疗这些脑疾病。