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

在这里，我们的目的是阐明调节谷氨酸能和gaba能神经元产生的分子机制，以及这些主要递质群体中各自的亚型。在端脑发育过程中，gaba能神经元主要起源于端脑腹侧，而谷氨酸能神经元主要起源于背侧。我们最近发现了这一规律的一些例外：gaba能和多巴胺能肾小球神经元起源于成人神经发生的吻侧迁移流（RMS） （Hack et al., 2005），一小部分gaba能神经元显然起源于大脑皮层（Malatesta et al., 2003）。在成人神经发生过程中，转录因子Pax6是gaba能和多巴胺能肾小球神经元生成的必要和充分条件（Hack et al., 2005），但在大脑皮层发育过程中，Pax6也参与谷氨酸能神经元的生成（Chapouton et al., 1999; Bibel et al., 2004; Kroll and O’leary, 2005）。因此，这些神经元亚型如何被指定的分子机制尚不清楚，也不清楚gaba能亚群如何以及何时被指定迁移到端脑的不同位置。此外，我们的目标是研究成人齿状回中谷氨酸能神经元产生的分子机制，并将其与嗅球中gaba能神经元形成的关键分子机制进行比较。我们将采用几种方法来阐明端脑中递质多样性的规范。首先，我们将使用可诱导的基于cre的命运映射来确定在发育和成年期间的哪个时期，哪些类型的gaba能神经元起源于哪个区域。接下来，我们将使用功能获得和功能丧失的方法来确定候选转录因子Olig2， Mash1, Dlx2， Emx2和Otx2在神经元亚型规范中的细胞自主功能，重点关注端脑的成人神经发生。这些知识也将用于损伤后特定类型神经元的再生。

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.