Intermediate progenitors in adult hippocampal neurogenesis: Tbr2 expression and coordinate regulation of neuronal output

Neurogenesis in the adult hippocampus is a highly regulated process that originates from multipotent progenitors in the subgranular zone ( SGZ). Currently, little is known about molecular mechanisms that regulate proliferation and differentiation in the SGZ. To study the role of transcription factors ( TFs), we focused on Tbr2 ( T- box brain gene 2), which has been implicated previously in developmental glutamatergic neurogenesis. In adult mouse hippocampus, Tbr2 protein and Tbr2- GFP ( green fluorescent protein) transgene expression were specifically localized to intermediate- stage progenitor cells ( IPCs), a type of transit amplifying cells. The Tbr2 + IPCs were highly responsive to neurogenic stimuli, more than doubling after voluntary wheel running. Notably, the Tbr2 + IPCs formed cellular clusters, the average size of which ( Tbr2 + cells per cluster) likewise more than doubled in runners. Conversely, Tbr2 + IPCs were selectively depleted by antimitotic drugs, known to suppress neurogenesis. After cessation of antimitotic treatment, recovery of neurogenesis was paralleled by recovery of Tbr2 + IPCs, including a transient rebound above baseline numbers. Finally, Tbr2 was examined in the context of additional TFs that, together, define a TF cascade in embryonic neocortical neurogenesis ( Pax6 -> Ngn2 -> Tbr2 -> NeuroD -> Tbr1). Remarkably, the same TF cascade was found to be linked to stages of neuronal lineage progression in adult SGZ. These results suggest that Tbr2 + IPCs play a major role in the regulation of adult hippocampal neurogenesis, and that a similar transcriptional program controls neurogenesis in adult SGZ as in embryonic cerebral cortex.