Tbr2-expressing intermediate progenitor cells in the adult mouse hippocampus are unipotent neuronal precursors with limited amplification capacity under homeostasis

doi:10.1007/s11515-015-1364-0

Front. Biol.

2015, Vol. 10

Issue (3) : 262-271 https://doi.org/10.1007/s11515-015-1364-0

RESEARCH ARTICLE

Tbr2-expressing intermediate progenitor cells in the adult mouse hippocampus are unipotent neuronal precursors with limited amplification capacity under homeostasis

Daniel A. Berg^1,^2,³,Ki-Jun Yoon^1,²,Brett Will¹,Alex Y. Xiao¹,Nam-Shik Kim^1,²,Kimberly M. Christian^1,²,Hongjun Song^1,^2,⁴,Guo-li Ming^1,^2,^4,^*(

)

1. Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3. Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Scheelev?g 2, 17 117 Stockholm, Sweden
4. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

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Abstract

Neurogenesis persists in two locations of the adult mammalian brain, the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus. In the adult subgranular zone, radial glial-like cells (RGLs) are multipotent stem cells that can give rise to both astrocytes and neurons. In the process of generating neurons, RGLs divide asymmetrically to give rise to one RGL and one intermediate progenitor cell (IPC). IPCs are considered to be a population of transit amplifying cells that proliferate and eventually give rise to mature granule neurons. The properties of individual IPCs at the clonal level are not well understood. Furthermore, it is not clear whether IPCs can generate astrocytes or revert back to RGLs, besides generating neurons. Here we developed a genetic marking strategy for clonal analysis and lineage-tracing of individual Tbr2-expressing IPCs in the adult hippocampus in vivo using Tbr2-CreER^T2 mice. Using this technique we identified Tbr2-CreER^T2 labeled IPCs as unipotent neuronal precursors that do not generate astrocytes or RGLs under homeostasis. Additionally, we showed that these labeled IPCs rapidly generate immature neurons in a synchronous manner and do not undergo a significant amount of amplification under homeostasis, in animals subjected to an enriched environment/running, or in animals with different age. In summary, our study suggests that Tbr2-expressing IPCs in the adult mouse hippocampus are unipotent precursors and rapidly give rise to immature neurons without major amplification.

Keywords adult neurogenesis Tbr2 clonal analysis lineage tracing enriched environment

Corresponding Author(s): Guo-li Ming

Online First Date: 09 June 2015 Issue Date: 23 June 2015

Cite this article:

Daniel A. Berg,Ki-Jun Yoon,Brett Will, et al. Tbr2-expressing intermediate progenitor cells in the adult mouse hippocampus are unipotent neuronal precursors with limited amplification capacity under homeostasis[J]. Front. Biol., 2015, 10(3): 262-271.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-015-1364-0
https://academic.hep.com.cn/fib/EN/Y2015/V10/I3/262

Fig.1 Tbr2-CreER^T2 mouse line as a genetic tool to specifically target individual Tbr2⁺ IPCs in the adult mouse dentate gyrus. (A) A schematic diagram illustrating the lineage relationships during adult neurogenesis in the mouse hippocampus and the expression of markers used in this study. (B) An illustration of the genetic approach used to label individual Tbr2⁺ IPCs. (C–G) Lineage tracing of Tbr2-expressing IPCs at the clonal level. Adult mice were given a single injection of tamoxifen and examined at different time points. Shown in C is a sample confocal image of GFP⁺ precursors and DAPI in the adult dentate gyrus at 1 dpi (Scale bar: 100 μm). Magnification of boxed area in C is shown in C’ (Scale bar: 10 μm). Shown in D is a sample confocal image of a Tbr2⁺GFP⁺ precursor at 1 dpi (Scale bar: 10 μm). Images of Tbr2 immunostaining and DAPI are shown in D’. Arrows point to GFP⁺ cells. Shown in E is a sample confocal image of a DCX⁺GFP⁺ precursor at 1 dpi (Scale bar: 10 μm). Images of DCX immunostaining and DAPI are shown in D’. Shown in F are percentages of GFP⁺ progenitor cells expressing Tbr2 and DCX at 1 dpi. Values represent mean±SEM (n = 3 dentate gyri). Shown in G is a summary of quantification of the number of GFP⁺ clones per dentate gyrus at different time points. Values represent mean±SEM (n = 5–8 dentate gyri).

Fig.2 Clonally labeled Tbr2⁺ IPCs rapidly change morphology and differentiate into immature neurons in the adult mouse dentate gyrus. (A–B) Time course of Tbr2 expression in GFP⁺ cells in the dentate gyrus of adult Tbr2-CreER^T2 mice upon a single injection of tamoxifen. Shown in A are sample confocal images of GFP, Tbr2 immunostaining and DAPI. Scale bar: 10 μm. Shown in B is a summary of percentages of GFP⁺ cells expressing Tbr2 at different time points. Values represent mean±SEM (n = 3–4 dentate gyri; ***p<0.001; One way ANOVA, Tukey’s multiple comparisons test). (C–D) Development of GFP⁺ cells in the dentate gyrus of adult Tbr2-CreER^T2 mice upon a single injection of tamoxifen. Shown in C are sample confocal images of GFP and DAPI. Scale bar: 20 μm. Shown in D is a summary of quantitative comparison of different cell types at different time points. Values represent mean±SEM (n = 6–8 dentate gyri).

Fig.3 Proliferative capacity of Tbr2⁺ IPCs in the adult mouse dentate gyrus. (A–B) Sample confocal image of GFP⁺ clones containing multiple cells at 1 dpi (A) and 15 dpi (B). Scale bars: 10 μm. (C) Distribution of the clone size at different time points after a single tamoxifen injection. Pie charts indicate percentages of clones of different size and bars indicates mean (1 dpi: n = 67; 2 dpi: n = 70; 4 dpi: n = 102; 6 dpi: n = 58; 15 dpi: n = 79 clones, 5–8 dentate gyri per time point; ***p<0.001; One way ANOVA, Tukey’s multiple comparisons test ). (D) A sample confocal image of an MCM2⁺ GFP⁺ cell at 1 dpi. Shown in D’ are images of GFP, MCM2 immunostaining and DAPI. Scale bar: 10 μm. (E) Summary of percentages of MCM2⁺ GFP⁺ cells at different time points after a single tamoxifen injection. Values represent mean±SEM (n = 3 dentate gyri; ***p<0.001; One way ANOVA, Turkeys multiple comparisons test).

Fig.4 Paradigm of enriched environment and running accelerates the differentiation of Tbr2⁺ IPCs in the adult mouse dentate gyrus. (A) A schematic illustration of the experimental paradigm used. (B–C) Sample confocal images of MCM2⁺ GFP⁺ cells in control animals (B) or animal subjected to enriched environment (EE, C) at 4 dpi. Scale bars: 20 μm. Shown in B’ and C’ are sample confocal images of GFP, MCM2 immunostaining and DAPI. Scale bars: 10 μm. (D) Summary of quantitative comparison of the clonal size at 4 dpi. Values represent mean±SEM (n = 6-8 dentate gyri). (E) Summary of quantitative comparison of percentages of MCM2⁺ cells among all GFP⁺ precursors. Values represent mean±SEM (n = 3 dentate gyri; *p<0.05; **p<0.01; Student?s t-test). (F) Summary of quantitative comparison of percentages of cell types observed in GFP⁺ clones at 4 dpi. Values represent mean±SEM (n = 6-8 dentate gyri; ***p<0.005; Student’s t-test).

Fig.5 Slower differentiation tempo of Tbr2⁺ IPCs in the dentate gyrus in older adult mice. (A–B) Sample confocal images of GFP⁺ immature neurons at 6 dpi from a 2 month-old mouse (A) and GFP⁺ neuroblasts at 6 dpi from a 6 month-old mouse (B). Scale bars: 20 μm. (C) Quantitative comparison of clonal size at 4 dpi. Values represent mean±SEM (n = 6 dentate gyri). (D) Quantitative comparison of percentages of cell types observed in GFP⁺ clones at 6 dpi. Values represent mean±SEM (n = 6 dentate gyri; **p<0.05; Student’s t-test).

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