Fate determinants for transmitter diversity in the developing and adult telencephalon: how to make GABAergic or glutamatergic neurons

发育中和成年端脑递质多样性的命运决定因素：如何产生 GABA 能或谷氨酸能神经元

• 批准号: 43598258
• 负责人: Professorin Dr. Magdalena Götz
• 金额: --
• 依托单位: Institut für Physiologische Genomik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/43598258?language=en
• 关键词: Fate; determinants; transmitter; diversity; developing

Here we aim to elucidate the molecular mechanisms regulating the generation of glutamatergic and GABAergic neurons, as well as respective subtypes amongst these major transmitter populations. During development of the telencephalon, GABAergic neurons originate mainly in the ventral telencephalon, while glutamatergic neurons originate dorsally. We have recently discovered some exceptions to this rule: GABAergic and dopaminergic glomerular neurons originate in the rostral migratory stream (RMS) in adult neurogenesis (Hack et al., 2005) and a small population of GABAergic neurons apparently originates within the cerebral cortex (Malatesta et al., 2003). The transcription factor Pax6 is necessary and sufficient for the specification of GABAergic and dopaminergic glomerular neurons in adult neurogenesis (Hack et al., 2005), but is also involved in the generation of glutamatergic neurons during development of the cerebral cortex (Chapouton et al., 1999; Bibel et al., 2004; Kroll and O’Leary, 2005). Thus, the molecular mechanisms how these neuronal subtypes are specified are not yet understood, neither is it clear how and when subsets of GABAergic that migrate to distinct locations in the telencephalon are specified. Moreover, we aim to address the molecular mechanisms responsible for the generation of glutamatergic neurons in the adult dentate gyrus in comparison with those crucial for adult neurogenesis of GABAergic neurons in the olfactory bulb. We will pursue several approaches to elucidate the specification of transmitter diversity in the telencephalon. First, we will use inducible Cre-based fate-mapping to determine which types of GABAergic neurons originate from which domain at which time during development and in adulthood. Next, we will use gain- and loss-of-function approaches to determine the cell-autonomous function of the candidate transcription factors Olig2, Mash1, Dlx2, Emx2 and Otx2 in neuronal subtype specification with a focus on adult neurogenesis in the telencephalon. This knowledge will also be employed towards regeneration of specific types of neurons after injury.

在这里，我们的目的是阐明调节的生成的谷氨酸能和GABA能神经元的分子机制，以及各自的亚型之间的这些主要的递质群体。在端脑发育过程中，GABA能神经元主要起源于端脑腹侧，而中脑能神经元则起源于背侧。我们最近发现了该规则的一些例外：GABA能和多巴胺能肾小球神经元起源于成人神经发生中的吻侧迁移流（RMS）（Hack等人，2005），并且少量GABA能神经元显然起源于大脑皮层内（Malatesta等人，2003年）。转录因子Pax 6对于成体神经发生中GABA能和多巴胺能肾小球神经元的特化是必要和充分的（Hack等人，2005），但也参与大脑皮层发育过程中多巴胺能神经元的产生（Chapouton等人，1999; Bibel等人，2004年; Kroll和O 'Leary，2005年）。因此，这些神经元亚型如何被指定的分子机制尚未被理解，也不清楚如何以及何时指定迁移到端脑中不同位置的GABA能亚群。此外，我们的目标是解决的分子机制，负责在成年齿状回的GABA能神经元的成年神经发生的嗅球中的GABA能神经元的生成相比。我们将采用几种方法来阐明端脑中发射器多样性的规范。首先，我们将使用可诱导的Cre为基础的命运映射，以确定哪种类型的GABA能神经元起源于哪个领域在发展过程中的时间和成年期。接下来，我们将使用增益和功能丧失的方法来确定候选转录因子Olig 2，Mash 1，Dlx 2，Emx 2和Otx 2在神经元亚型规范中的细胞自主功能，重点是端脑中的成人神经发生。这些知识也将用于损伤后特定类型神经元的再生。