Regional Control of Telencephalic Neuronal Diversity

端脑神经元多样性的区域控制

• 批准号: 7001333
• 负责人: KENNETH J CAMPBELL
• 金额: $ 32.74万
• 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/7001333
• 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）：成熟的中枢神经系统由多种不同的神经元亚型组成。神经元亚型的多样性是中枢神经系统控制的许多复杂功能的基础。发育中的中枢神经系统中神经元多样性的产生似乎受到神经元亚型的局部产生以及这些亚型随后通过迁移在大脑内的分布的控制。局部神经元的生成取决于离散神经元祖细胞域的形成和输出。该提案将重点关注端脑外侧神经节隆起（LGE）中的两个这样的祖细胞域。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 则由 LIM 同源框基因 Islet1 (Isl1) 标记。我们最近发现了 dLGE 的一个新标记，称为 Sp8，它是 Sp1 转录因子家族的新成员。我们之前的工作使我们提出，dLGE 和 vLGE 产生不同的神经元后代，分别是嗅球中间神经元和纹状体投射神经元。该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检验这一假设。具体目标 1 将使用遗传命运图谱来追踪源自表达 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度表达来确定 Sp8 在 dLGE 和嗅球中间神经元发育中的作用。最后，特定目标 3 将使用体内和体外条件诱变和过度表达来检查 Isl1 对 vLGE 发育的要求。许多影响儿童和年轻人的神经精神疾病，如注意力缺陷多动障碍（ADHD）、抽动秽语综合症和精神分裂症，被认为至少部分是由纹状体功能异常造成的。最近的想法支持这样的观点，即这些大脑疾病可能至少部分是由于大脑发育异常造成的。因此，了解调节 LGE 神经元多样性的机制可能有助于更好地理解和治疗这些大脑疾病。