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

在这里，我们旨在阐明调节谷氨酸和GABA能神经元产生的分子机制，以及这些主要递质群体中的各自亚型。在端脑发育过程中，GABA能神经元主要起源于端脑腹侧，谷氨酸能神经元主要起源于背侧。我们最近发现了这一规则的一些例外：在成人神经发生中，GABA能和多巴胺能肾小球神经元起源于嘴迁移流(RMS)(Hack等人，2005年)，少量GABA能神经元显然起源于大脑皮层(Malatesta等人，2003年)。转录因子Pax6是成人神经发生中GABA能和多巴胺能肾小球神经元的必要条件和充分条件(Hack等人，2005年)，但也参与大脑皮层发育过程中谷氨酸能神经元的产生(Chapouton等人，1999；Bibel等人，2004；Kroll和O‘Leary，2005)。因此，这些神经元亚型是如何被指定的分子机制还不清楚，也不清楚GABA能亚群是如何以及何时迁移到端脑中不同位置的。此外，我们的目标是研究负责成年齿状回谷氨酸能神经元产生的分子机制，并与那些对成年嗅球GABA能神经元发生至关重要的分子机制进行比较。我们将采用几种方法来阐明端脑中递质多样性的特性。首先，我们将使用可诱导的基于Cre的命运映射来确定哪些类型的GABA能神经元在发育期间和成年期的哪个时间起源于哪个区域。接下来，我们将使用功能获得和功能丧失的方法来确定神经元亚型规范中候选转录因子Orig2、Mash1、Dlx2、Emx2和OTX2的细胞自主功能，重点是端脑中的成年神经发生。这一知识也将用于损伤后特定类型神经元的再生。

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.