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

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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.