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The Journal of Neuroscience, April 2, 2008, 28(14):3707-3717; doi:10.1523/JNEUROSCI.4280-07.2008

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Development/Plasticity/Repair
Intermediate Progenitors in Adult Hippocampal Neurogenesis: Tbr2 Expression and Coordinate Regulation of Neuronal Output

Rebecca D. Hodge,¹ Thomas D. Kowalczyk,¹ Susanne A. Wolf,² Juan M. Encinas,³ Caitlin Rippey,¹ Grigori Enikolopov,³ Gerd Kempermann,² and Robert F. Hevner¹

¹Departments of Neurological Surgery and Pathology, University of Washington School of Medicine, Seattle, Washington 98101-1304, ²Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany, and ³Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724

Correspondence should be addressed to Robert F. Hevner, Seattle Children's Hospital Research Institute, Room 828, 1900 Ninth Avenue, Seattle, WA 98101-1304. Email: rhevner{at}u.washington.edu

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.

Key words: transcription factor; dentate gyrus; transit amplifying cells; glutamatergic neurons; subgranular zone; type-2 cells

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Received Sept. 18, 2007; revised Jan. 21, 2008; accepted Feb. 23, 2008.

Correspondence should be addressed to Robert F. Hevner, Seattle Children's Hospital Research Institute, Room 828, 1900 Ninth Avenue, Seattle, WA 98101-1304. Email: rhevner{at}u.washington.edu

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