Regionalization of adult neurogenesis

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.