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Brill, Monika (2009): Regionalization of adult neurogenesis: The role of the transcription factors Dlx2 and Pax6 in the murine subependymal zone. Dissertation, LMU München: Faculty of Biology
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Abstract

The vast majority of neurons in the murine brain are generated during embryonic neurogenesis. However, at least two neurogenic niches continue to produce specific types of neurons throughout life. The adult dentate gyrus harbours stem cells that generate dentate granule neurons and the subependymal zone produces distinct types of olfactory interneurons. The adult neurogenic subependymal zone is derived from the embryonic dorsal and ventral subventricular zone of the telencephalon, i. e. progenitor domains which generate both the ventral and dorsal glutamatergic and GABAergic neurons, respectively. While a cascade of transcription factors beginning with Pax6 governs the generation of glutamatergic cortical neurons, transcription factors of the Dlx family are crucial for the embryonic neurogenesis of GABAergic neurons. Notably, Pax6 and Dlx transcription factors factors are expressed in the adult subependymal zone. In this study I investigated the regionalization of the adult subependymal neurogenic niche in regard to Pax6 and Dlx and I examined the role of these factors in neuronal subtype specification. Consistent with their embryonic origin progenitors in the adult brain express Dlx1 and Dlx2 in the lateral, but not the dorsal subependymal zone. Using retroviral vectors I demonstrated that Dlx2 is necessary for neurogenesis of virtually all olfactory interneurons arising from the lateral subependymal zone. Beyond its function in generic neurogenesis, Dlx2 plays a crucial role in neuronal subtype specification in the adult olfactory bulb promoting specification of dopaminergic interneurons. Strikingly, Dlx2 requires interaction with Pax6, as Pax6 deletion blocks Dlx2 mediated neuronal specification. Of note, however, Pax6 protein is expressed in a gradient being especially abundant in dorsal regions of the adult subpenedymal zone. While playing obviously a role in the genesis of GABAergic interneurons, I also investigated whether the dorsal subependymal zone could give rise to glutamatergic neurons which have so far been overlooked. Surprisingly, progenitors located mainly in dorso-rostral regions of the subependymal zone express transcription factors previously linked to glutamatergic neurogenesis like Pax6 → Neurogenin2 → Tbr2 → Tbr1. These neurons migrate along the rostral migratory stream and integrate into the glomerular layer of the olfactory bulb. Finally, I provide evidence that these Tbr2-positive cells could become recruited following cortical lesions where callosal projection neurons are depleted.