The Roles of Gsh1 and Gsh2 Genes in Telencephalic Neurogenesis

哺乳动物的端脑代表了大脑中细胞多样性最强的区域， 尤其是在神经元亚型方面。产生这种多样性的一个可能的机制是它的 旷日持久的神经发生时间表。事实上，端脑神经发生在出生后持续，甚至 进入成年期，至少在嗅球和海马体中。这项提案将审查两个人的角色 同源异型盒基因Gsh1和Gsh2及其在纹状体投射神经元和 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，但嗅觉 鳞茎中间神经元在胚胎和出生后两个阶段都会产生。我们假设谷胱甘肽 基因在时间上不同的时间点指定了这两种神经元亚型，前三个目标是 旨在测试这一点。在第一个目标中，我们将检查Gsh2指定纹状体的时间窗口 投射神经前体细胞与其嗅球间神经元对应细胞的比较。第二个目标将检查 Gsh1在促进端脑祖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神经发生中的作用。 最近的研究发现，表达Gsh2的祖细胞也会在围产期产生少突胶质细胞 各阶段。我们推测，这只发生在胚胎晚期和早期Gsh2下调之后。 出生后阶段。目标4将通过执行条件失活和过度表达来检查这种可能性 Gsh2在围产期、活体和体外出生时的表达。 某些神经发育障碍，如抽动症、注意缺陷多动 精神障碍(ADHD)和强迫症(OCD)被认为至少部分原因是 纹状体的功能/发育异常。此外，嗅球中间神经元 使它们的祖细胞成为细胞工程和细胞工程的有吸引力的候选人 替代疗法。从而更好地了解纹状体和嗅球的发育和特异性 GSH基因在这些过程中扮演的角色可能会提供对某些大脑的更好理解 紊乱和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.