The Roles of Gsh1 and Gsh2 Genes in Telencephalic Neurogenesis

哺乳动物的端脑是大脑中细胞多样性最丰富的区域， 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 神经发生的时间表延长。事实上，端脑神经发生持续到出生后， 至少在嗅球和海马体中是这样的。本建议将审查两个机构的作用， 同源盒基因Gsh 1和Gsh 2及其在纹状体投射神经元神经发生中的作用， 嗅球中间神经元。虽然纹状体神经发生只发生在胚胎时间点，嗅觉 球中间神经元在胚胎和出生后阶段产生。我们假设谷胱甘肽 基因在时间上不同的时间点指定这两种神经元亚型，前3个目标是 设计来测试这个。在第一个目标中，我们将检查Gsh 2指定纹状体的时间窗， 投射神经元祖细胞与它们的嗅球中间神经元对应物。第二个目标将审查 Gsh 1在促进端脑前体细胞分化中的作用。目标3将审查这一要求 GSH基因在调节出生后脑室下区的神经发生。 最近的研究发现，表达Gsh 2的祖细胞也能在围产期产生少突胶质细胞。 阶段我们推测这只发生在胚胎晚期和胚胎早期Gsh 2下调之后。 产后阶段。AIM 4将通过进行条件失活和过表达来检验这种可能性 Gsh 2在围产期出生在体内和体外。 某些神经发育障碍，如图雷特综合征，注意力缺陷多动， 注意力缺陷多动障碍（ADHD）和强迫症（OCD）被认为至少部分是由于 纹状体功能/发育异常。此外，事实上，嗅球中间神经元是 成年后产生的细胞使其祖细胞成为细胞工程和细胞移植的有吸引力的候选者。 替代疗法因此，更多的了解纹状体和嗅球的发展和具体的 GSH基因在这些过程中所起的作用可能会使我们更好地了解某些大脑 以及可能的大脑修复策略。

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. We hypothesize that the Gsh genes specify these two neuronal subtypes at temporally distinct time points and the first 3 aims are designed to test this. In the first aim, we will examine the time windows in which Gsh2 specifies striatal projection neuron progenitors vs their olfactory bulb interneuron counterparts. The second aim will examine the role of Gsh1 in promoting differentiation of telencephalic progenitors. Aim 3 will examine the requirement for Gsh genes in regulating neurogenesis within the postnatal subventricular zone. Recent work has found that Gsh2-expressing progenitors also give rise to oligodendrocytes at perinatal stages. We hypothesize that this only occurs after the down-regulation of Gsh2 at late embryonic and early postnatal stages. Aim 4 will examine this possibility by performing conditional inactivation and overexpression of Gsh2 at perinatal stages birth in vivo and in vitro. 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 knowlegde 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.