Roles of Gsh1 & Gsh2 in Telencephalic Neurogenesis

描述（由申请人提供）：哺乳动物端脑代表了显示最多细胞多样性的脑区域，特别是关于神经元亚型。产生这种多样性的一个可能机制是其延长的神经发生时间表。事实上，端脑神经发生在出生后甚至成年后仍在继续，至少在嗅球和海马中是这样。本研究将探讨两个同源异型盒基因Gsh 1和Gsh 2在纹状体投射神经元和嗅球中间神经元发生中的作用。虽然纹状体神经发生只发生在胚胎时间点，嗅球中间神经元产生在胚胎和出生后阶段。最近的工作发现，Gsh 2表达的祖细胞也会在围产期产生少突胶质细胞，这与Gsh 2下调的时期相关。我们推测GSH基因促进胚胎和出生后大脑中的神经发生，同时抑制少突胶质细胞的发育。本提案中的四个目标旨在解决这一假设。第一个目标，将检查Gsh 2指定纹状体投射神经元祖细胞和嗅球中间神经元对应物的时间窗口，以及它在胚胎发生过程中对少突胶质细胞特化的负调控。第二个目的是研究Gsh 1在促进端脑祖细胞分化中的作用。目的3研究Gsh 2下游Mash 1和Dlx 1/2基因在端脑发育中的作用。最后，目的4将检查GSH基因在调节神经发生和少突神经发生在出生后脑室下区的要求。某些神经发育障碍，例如图雷特综合征、注意力缺陷多动障碍（ADHD）和强迫症（OCD）被认为至少部分地由纹状体的异常功能/发育引起。此外，嗅球中间神经元在成年期产生的事实使其祖细胞成为细胞工程和细胞替代疗法的有吸引力的候选者。因此，更多的知识纹状体和嗅球的发展和特定的作用，GSH基因在这些过程中发挥可能提供更好的理解某些大脑疾病和可能的大脑修复策略。公共卫生相关性：端脑是大脑中与认知和自主运动最相关的区域。控制这些过程的主要端脑结构之一是纹状体（也称为尾壳核）。纹状体功能障碍发生在许多神经退行性疾病中，例如帕金森病和亨廷顿舞蹈病，导致异常运动，在某些情况下导致痴呆。此外，某些神经发育障碍，如图雷特综合征、注意力缺陷多动障碍（ADHD）和强迫症（OCD）已被认为是由纹状体的功能障碍和/或发育改变引起的。产生纹状体投射神经元的胚胎区域也产生向嗅球迁移的中间神经元。与纹状体投射神经元不同，嗅球中间神经元在动物的一生中不断产生。这一事实导致了一个不断增长的研究领域，该领域试图分离和表征在成人大脑中产生这些神经元的神经干细胞。这些研究的希望是，干细胞可以用于某些神经退行性疾病（如帕金森病和亨廷顿病）的细胞替代策略。然而，鲜为人知的是，无论是纹状体投射神经元或嗅球中间神经元的规格。因此，更多的知识，以分子机制（如GSH 1和GSH 2）的基础上产生这两种神经元亚型可能有助于更好地理解上述脑疾病，以及提供脑修复策略的可能性。

DESCRIPTION (provided by applicant): The mammalian telencephalon represents the region of the brain that displays the most cellular diversity, particularly with respect to neuronal subtypes. One likely mechanism for generating this diversity is its protracted schedule of neurogenesis. Indeed, telencephalic neurogenesis continues postnatally and even into adulthood, at least in the olfactory bulb and hippocampus. This proposal will examine the role of two homeobox genes, Gsh1 and Gsh2 and their role in the neurogenesis of striatal projection neurons and olfactory bulb interneurons. While striatal neurogenesis occurs exclusively at embryonic time points, olfactory bulb interneurons are generated at both embryonic and postnatal stages. Recent work has found that Gsh2-expressing progenitors also give rise to oligodendrocytes at perinatal stages, this correlates with the period when Gsh2 is down-regulating. We hypothesize that Gsh genes promote neurogenesis in the embryonic and postnatal brain while repressing oligodendrocyte development. The four aims in this proposal are designed to address this hypothesis. The first aim, will examine the time windows in which Gsh2 specifies striatal projection neuron progenitors and their olfactory bulb interneuron counterparts as well as it negative regulation of oligodendrocyte specification during embryogenesis. The second aim will examine the role of Gsh1 in promoting differentiation of telencephalic progenitors. Aim 3 will examine the role of Mash1 and Dlx1/2 genes down-stream of Gsh2 in telencephalic development. Finally, aim 4 will examine the requirement for Gsh genes in regulating neurogenesis and oligodendrogenesis within the postnatal subventricular zone. Certain neurodevelopmental disorders such as Tourette's syndrome, attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD) are thought to result at least in part from abnormal function/development of the striatum. Additionally, the fact that olfactory bulb interneurons are generated into adulthood has made their progenitors attractive candidates for cellular engineering and cell replacement therapies. Thus greater knowledge of striatal and olfactory bulb development and the specific roles that Gsh genes play in these processes is likely to provide a better understanding of certain brain disorders and possible brain repair strategies. PUBLIC HEALTH RELEVANCE: The telencephalon represents the region of the brain most concerned with cognition and voluntary movement. One of the major telencephalic structures controlling these processes is the striatum (also known as the caudate-putamen). Malfunction of the striatum occurs in a number of neurodegenerative disorders such as Parkinson's disease and Huntington's chorea, leading to abnormal movements and in some cases dementia. Moreover, certain neurodevelopmental disorders, such as Tourette's syndrome, attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD) have been suggested to result from malfunction and/or altered development of the striatum. The embryonic region that gives rise to the striatal projection neurons also produces interneurons that migrate rostrally to the olfactory bulb. Unlike the striatal projection neurons, the olfactory bulb interneurons are continuously produced throughout the lifetime of the animal. This fact has led to a growing field of research, which is attempting to isolate and characterize the neural stem cells that generate these neurons in the adult brain. The hope of these studies is that the stem cells could be used for cell replacement strategies in certain neurodegenerative diseases (e.g. Parkinson's and Huntington's disease). Little is known, however, about the specification of either striatal projection neurons or olfactory bulb interneurons. Thus greater knowledge as to the molecular mechanisms (e.g. Gsh1 and Gsh2) underlying the generation of these two neuronal subtypes is likely to contribute to a better understanding of the above mentioned brain disorders as well as providing possibilities for brain repair strategies.