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.
Hodge
Rebecca D
RD
Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington 98101-1304, USA.
Kowalczyk
Thomas D
TD
Wolf
Susanne A
SA
Encinas
Juan M
JM
Rippey
Caitlin
C
Enikolopov
Grigori
G
Kempermann
Gerd
G
Hevner
Robert F
RF
D053687:Adult Stem Cells / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D016000:Cluster Analysis; D005260:Female; D015870:Gene Expression; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D012420:Running / Q000502:physiology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D043324:beta-Fructofuranosidase / Q000494:pharmacology
C491198:Eomes protein, mouse; D009419:Nerve Tissue Proteins; D020825:T-Box Domain Proteins; D049452:Green Fluorescent Proteins; D043324:beta-Fructofuranosidase; D001973:Bromodeoxyuridine