Regional Control of Telencephalic Neuronal Diversity

描述(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。这种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。在发育中的中枢神经系统中神经元多样性的产生似乎受神经元亚型的局部产生以及随后这些亚型通过迁移在脑内的分布所控制。局部神经元的产生依赖于离散的神经元前体结构域的形成和输出。这项提议将集中在端脑的外侧神经节隆起(LGE)中的两个这样的祖细胞结构域。大脑发育中的这一区域产生了纹状体的投射神经元以及嗅球的中间神经元。基因表达研究表明，LGE结构域可分为背侧结构域(DLGE)和腹侧结构域(VLGE)。DLGE表达ETS转录因子基因Er81，而vLGE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转录因子家族的一个新成员。我们以前的工作导致我们提出dLGE和vLGE分别产生不同的神经元后代，即嗅球内神经元和纹状体投射神经元。这一提议的主要目标是通过以下三个具体目标中概述的实验来检验这一假设。特定目的1将使用遗传命运图谱来跟踪来自Isl1表达vLGE或SP8表达dLGE的神经元。具体目标2将通过条件突变和过度表达来确定SP8在dLGE和嗅球间神经元发育中的作用。最后，特殊目标3将使用条件突变和体内和体外的过度表达来检查IsL1对vLGE发育的要求。许多神经精神疾病，如注意力缺陷多动障碍(ADHD)、抽动症和精神分裂症，影响到儿童和年轻人，被认为至少部分是由于纹状体功能异常造成的。最近的想法支持这样一种观点，即这些大脑障碍可能至少部分归因于大脑发育的异常。因此，对LGE中调节神经元多样性的机制的了解可能有助于更好地理解和可能治疗这些大脑疾病。

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.