Regional Control of Telencephalic Neuronal Diversity

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。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是由神经元亚型的局部产生和随后这些亚型在脑内的迁移分布所控制的。局部神经元的产生依赖于离散神经元祖域的形成和输出。这一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）。大脑发育的这个区域产生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表达LIM同源盒基因Islet1 （Isl1）。我们最近发现了一个名为Sp8的dLGE新标记，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分别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。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检验这一假设。特异性目标1将使用遗传命运定位来跟踪来自表达isl1的vlge或表达sp8的dLGE的神经元。特异性Aim 2将通过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，Specific Aim 3将在体内和体外通过条件诱变和过表达来研究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，如注意缺陷多动障碍（ADHD）、妥瑞氏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引起的。最近的研究支持这样一种观点，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脑部疾病。

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.