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Age-dependent kinetics of dentate gyrus neurogenesis in the absence of cyclin D2.

Ansorg A, Witte OW, Urbach A - BMC Neurosci (2012)

Bottom Line: Cell cycle progression is governed by the successive expression, activation and degradation of regulatory proteins.This was paralleled by a reduction in granule cell numbers, in the volume of the granule cell layer as well as in apoptotic cell death.The present study suggests that hippocampal neurogenesis becomes increasingly dependent on cD2 during early postnatal development.

View Article: PubMed Central - HTML - PubMed

Affiliation: Hans Berger Department of Neurology, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany.

ABSTRACT

Background: Adult neurogenesis continuously adds new neurons to the dentate gyrus and the olfactory bulb. It involves the proliferation and subsequent differentiation of neuronal progenitors, and is thus closely linked to the cell cycle machinery. Cell cycle progression is governed by the successive expression, activation and degradation of regulatory proteins. Among them, D-type cyclins control the exit from the G1 phase of the cell cycle. Cyclin D2 (cD2) has been shown to be required for the generation of new neurons in the neurogenic niches of the adult brain. It is differentially expressed during hippocampal development, and adult cD2 knock out (cD2KO) mice virtually lack neurogenesis in the dentate gyrus and olfactory bulb. In the present study we examined the dynamics of postnatal and adult neurogenesis in the dentate gyrus (DG) of cD2KO mice. Animals were injected with bromodeoxyuridine at seven time points during the first 10 months of life and brains were immunohistochemically analyzed for their potential to generate new neurons.

Results: Compared to their WT litters, cD2KO mice had considerably reduced numbers of newly born granule cells during the postnatal period, with neurogenesis becoming virtually absent around postnatal day 28. This was paralleled by a reduction in granule cell numbers, in the volume of the granule cell layer as well as in apoptotic cell death. CD2KO mice did not show any of the age-related changes in neurogenesis and granule cell numbers that were seen in WT litters.

Conclusions: The present study suggests that hippocampal neurogenesis becomes increasingly dependent on cD2 during early postnatal development. In cD2KO mice, hippocampal neurogenesis ceases at a time point at which the tertiary germinative matrix stops proliferating, indicating that cD2 becomes an essential requirement for ongoing neurogenesis with the transition from developmental to adult neurogenesis. Our data further support the notion that adult neurogenesis continuously adds new neurons to the hippocampal network, hence increasing cell density of the DG.

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Examples of Nissl-stained sections spanning the rostro-caudal axis of the brain illustrating differences in overall brain structure of WT and cD2KO mice. Positions relative to bregma are marked on the left. The gross morphology of cD2KO brains appears to be close to normal but brains of cD2KO mice are smaller than that of their WT litters. Size differences are already apparent at P35.
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Figure 2: Examples of Nissl-stained sections spanning the rostro-caudal axis of the brain illustrating differences in overall brain structure of WT and cD2KO mice. Positions relative to bregma are marked on the left. The gross morphology of cD2KO brains appears to be close to normal but brains of cD2KO mice are smaller than that of their WT litters. Size differences are already apparent at P35.

Mentions: Volumetric estimation of the entire brain, hippocampus and the dentate GCL in cD2KO mice revealed significant differences compared to WT litters at all ages examined. On average, the brain was smaller by ~26% (Figures 2 and 3A), the hippocampus by ~31% (Figure 3B) and the dentate GCL by ~49% (Figure 3C). These differences were already present in 1 month-old animals (P7 group). In both genotypes, brain volume remained fairly constant over time (Figure 3A). We only detected a slight increase from P35 to P118 (p = 0.011) and P88 to P288 (p = 0.018) in WT mice, and from P42 to P68 (p = 0.007) and P42 to P288 (p = 0.029) in cD2KO mice. The volume of the HC increased continuously in WT mice, especially when comparing ages of P88 and younger to P288 (P88 vs. P288: p = 0.042; Figure 3B). In contrast, the HC volume of cD2KO mice showed no significant age-related differences. Similarly, the dentate GCL volume did not change with increasing age, independent of genotype (Figure 3C).


Age-dependent kinetics of dentate gyrus neurogenesis in the absence of cyclin D2.

Ansorg A, Witte OW, Urbach A - BMC Neurosci (2012)

Examples of Nissl-stained sections spanning the rostro-caudal axis of the brain illustrating differences in overall brain structure of WT and cD2KO mice. Positions relative to bregma are marked on the left. The gross morphology of cD2KO brains appears to be close to normal but brains of cD2KO mice are smaller than that of their WT litters. Size differences are already apparent at P35.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3403990&req=5

Figure 2: Examples of Nissl-stained sections spanning the rostro-caudal axis of the brain illustrating differences in overall brain structure of WT and cD2KO mice. Positions relative to bregma are marked on the left. The gross morphology of cD2KO brains appears to be close to normal but brains of cD2KO mice are smaller than that of their WT litters. Size differences are already apparent at P35.
Mentions: Volumetric estimation of the entire brain, hippocampus and the dentate GCL in cD2KO mice revealed significant differences compared to WT litters at all ages examined. On average, the brain was smaller by ~26% (Figures 2 and 3A), the hippocampus by ~31% (Figure 3B) and the dentate GCL by ~49% (Figure 3C). These differences were already present in 1 month-old animals (P7 group). In both genotypes, brain volume remained fairly constant over time (Figure 3A). We only detected a slight increase from P35 to P118 (p = 0.011) and P88 to P288 (p = 0.018) in WT mice, and from P42 to P68 (p = 0.007) and P42 to P288 (p = 0.029) in cD2KO mice. The volume of the HC increased continuously in WT mice, especially when comparing ages of P88 and younger to P288 (P88 vs. P288: p = 0.042; Figure 3B). In contrast, the HC volume of cD2KO mice showed no significant age-related differences. Similarly, the dentate GCL volume did not change with increasing age, independent of genotype (Figure 3C).

Bottom Line: Cell cycle progression is governed by the successive expression, activation and degradation of regulatory proteins.This was paralleled by a reduction in granule cell numbers, in the volume of the granule cell layer as well as in apoptotic cell death.The present study suggests that hippocampal neurogenesis becomes increasingly dependent on cD2 during early postnatal development.

View Article: PubMed Central - HTML - PubMed

Affiliation: Hans Berger Department of Neurology, Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany.

ABSTRACT

Background: Adult neurogenesis continuously adds new neurons to the dentate gyrus and the olfactory bulb. It involves the proliferation and subsequent differentiation of neuronal progenitors, and is thus closely linked to the cell cycle machinery. Cell cycle progression is governed by the successive expression, activation and degradation of regulatory proteins. Among them, D-type cyclins control the exit from the G1 phase of the cell cycle. Cyclin D2 (cD2) has been shown to be required for the generation of new neurons in the neurogenic niches of the adult brain. It is differentially expressed during hippocampal development, and adult cD2 knock out (cD2KO) mice virtually lack neurogenesis in the dentate gyrus and olfactory bulb. In the present study we examined the dynamics of postnatal and adult neurogenesis in the dentate gyrus (DG) of cD2KO mice. Animals were injected with bromodeoxyuridine at seven time points during the first 10 months of life and brains were immunohistochemically analyzed for their potential to generate new neurons.

Results: Compared to their WT litters, cD2KO mice had considerably reduced numbers of newly born granule cells during the postnatal period, with neurogenesis becoming virtually absent around postnatal day 28. This was paralleled by a reduction in granule cell numbers, in the volume of the granule cell layer as well as in apoptotic cell death. CD2KO mice did not show any of the age-related changes in neurogenesis and granule cell numbers that were seen in WT litters.

Conclusions: The present study suggests that hippocampal neurogenesis becomes increasingly dependent on cD2 during early postnatal development. In cD2KO mice, hippocampal neurogenesis ceases at a time point at which the tertiary germinative matrix stops proliferating, indicating that cD2 becomes an essential requirement for ongoing neurogenesis with the transition from developmental to adult neurogenesis. Our data further support the notion that adult neurogenesis continuously adds new neurons to the hippocampal network, hence increasing cell density of the DG.

Show MeSH
Related in: MedlinePlus