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The critical role of cyclin D2 in adult neurogenesis.

Kowalczyk A, Filipkowski RK, Rylski M, Wilczynski GM, Konopacki FA, Jaworski J, Ciemerych MA, Sicinski P, Kaczmarek L - J. Cell Biol. (2004)

Bottom Line: In contrast, genetic ablation of cyclin D1 does not affect adult neurogenesis.In contrast, all three cyclin D mRNAs are present in the cultures derived from 5-day-old hippocampi, when developmental neurogenesis in the dentate gyrus takes place.Thus, our results reveal the existence of molecular mechanisms discriminating adult versus developmental neurogeneses.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Neurobiology, Nencki Institute, 02-093 Warsaw, Poland.

ABSTRACT
Adult neurogenesis (i.e., proliferation and differentiation of neuronal precursors in the adult brain) is responsible for adding new neurons in the dentate gyrus of the hippocampus and in the olfactory bulb. We describe herein that adult mice mutated in the cell cycle regulatory gene Ccnd2, encoding cyclin D2, lack newly born neurons in both of these brain structures. In contrast, genetic ablation of cyclin D1 does not affect adult neurogenesis. Furthermore, we show that cyclin D2 is the only D-type cyclin (out of D1, D2, and D3) expressed in dividing cells derived from neuronal precursors present in the adult hippocampus. In contrast, all three cyclin D mRNAs are present in the cultures derived from 5-day-old hippocampi, when developmental neurogenesis in the dentate gyrus takes place. Thus, our results reveal the existence of molecular mechanisms discriminating adult versus developmental neurogeneses.

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High level of neurogenesis in DG of 5-d-old cyclin D2–deficient animals; 3-d-old animals injected with BrdU and analyzed 2 d later. Nissl analysis of mutants (b) and WT controls (a). (c and d) BrdU labeling in the DG. (e) Differential expression of cyclins D in developing and adult hippocampal neuronal precursors. Expression of cyclin D mRNAs in neurosphere cultures derived from hippocampi of 5-d- and 3-mo-old WT mice. In the adult material only the cyclin D2 mRNA is expressed. (f) Colabeling of nestin (green) and cyclin D2 mRNA (red) in WT DG SGZ. A double-positive cell is shown. The image has been scanned at high resolution (100× objective, 1.4 NA) with a high zoom factor together with two additional cross-sections through the entire confocal stack, taken at the levels indicated by vertical and horizontal blue lines that demonstrate overlapping nestin immunoreactivity and cyclin D2 mRNA signals within the whole cell body. Blue shows DAPI staining revealing the cell nucleus. Bar, 5 μm.
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fig4: High level of neurogenesis in DG of 5-d-old cyclin D2–deficient animals; 3-d-old animals injected with BrdU and analyzed 2 d later. Nissl analysis of mutants (b) and WT controls (a). (c and d) BrdU labeling in the DG. (e) Differential expression of cyclins D in developing and adult hippocampal neuronal precursors. Expression of cyclin D mRNAs in neurosphere cultures derived from hippocampi of 5-d- and 3-mo-old WT mice. In the adult material only the cyclin D2 mRNA is expressed. (f) Colabeling of nestin (green) and cyclin D2 mRNA (red) in WT DG SGZ. A double-positive cell is shown. The image has been scanned at high resolution (100× objective, 1.4 NA) with a high zoom factor together with two additional cross-sections through the entire confocal stack, taken at the levels indicated by vertical and horizontal blue lines that demonstrate overlapping nestin immunoreactivity and cyclin D2 mRNA signals within the whole cell body. Blue shows DAPI staining revealing the cell nucleus. Bar, 5 μm.

Mentions: We have also investigated the effect of cyclin D2 mutation on the overall brain structure. We have found that the mutant brain is smaller by ∼25%, whereas the weight of the whole mice was lower by no more than 10%, when comparing the D2 KO and WT animals (Fig. 3). These size reductions are already evident in the brains of 2-wk-old mice (unpublished data). The overall brain structure of the D2 mutants appeared close to normal, although such brain regions as hippocampus, occipital cortex, cerebellum, and OB in particular were significantly smaller in mutants than in the WT mice (Fig. 3), whereas the lateral ventricles were expanded (Fig. 3, d and h). Notably, this phenotype is strikingly reminiscent of the effects of the orphan nuclear receptor TLX deficiency that is also lacking adult neurogenesis in the brain (Shi et al., 2004). In OB, the size reduction did associate with a well-defined and prominent abnormality in anatomic structure. As evidenced by Nissl-stained preparations (Fig. 3, b, c, f, and g), there was a striking decrease in cell density in the internal granular layer, and, to a lesser extent, a decrease in number of periglomerular granule cells. In the former layer, the characteristic striated aggregations of granule interneurons were clearly disrupted. Other neuronal populations, including mitral cells, appeared not to be disturbed. The abnormalities in OB structure that are evident in adult mice are also present at P5 (unpublished data). However, hippocampal DG of 5-d-old mice was not strikingly different between WT and D2 KO with plentiful neurogenesis also in the latter (Fig. 4, b and d).


The critical role of cyclin D2 in adult neurogenesis.

Kowalczyk A, Filipkowski RK, Rylski M, Wilczynski GM, Konopacki FA, Jaworski J, Ciemerych MA, Sicinski P, Kaczmarek L - J. Cell Biol. (2004)

High level of neurogenesis in DG of 5-d-old cyclin D2–deficient animals; 3-d-old animals injected with BrdU and analyzed 2 d later. Nissl analysis of mutants (b) and WT controls (a). (c and d) BrdU labeling in the DG. (e) Differential expression of cyclins D in developing and adult hippocampal neuronal precursors. Expression of cyclin D mRNAs in neurosphere cultures derived from hippocampi of 5-d- and 3-mo-old WT mice. In the adult material only the cyclin D2 mRNA is expressed. (f) Colabeling of nestin (green) and cyclin D2 mRNA (red) in WT DG SGZ. A double-positive cell is shown. The image has been scanned at high resolution (100× objective, 1.4 NA) with a high zoom factor together with two additional cross-sections through the entire confocal stack, taken at the levels indicated by vertical and horizontal blue lines that demonstrate overlapping nestin immunoreactivity and cyclin D2 mRNA signals within the whole cell body. Blue shows DAPI staining revealing the cell nucleus. Bar, 5 μm.
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Related In: Results  -  Collection

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fig4: High level of neurogenesis in DG of 5-d-old cyclin D2–deficient animals; 3-d-old animals injected with BrdU and analyzed 2 d later. Nissl analysis of mutants (b) and WT controls (a). (c and d) BrdU labeling in the DG. (e) Differential expression of cyclins D in developing and adult hippocampal neuronal precursors. Expression of cyclin D mRNAs in neurosphere cultures derived from hippocampi of 5-d- and 3-mo-old WT mice. In the adult material only the cyclin D2 mRNA is expressed. (f) Colabeling of nestin (green) and cyclin D2 mRNA (red) in WT DG SGZ. A double-positive cell is shown. The image has been scanned at high resolution (100× objective, 1.4 NA) with a high zoom factor together with two additional cross-sections through the entire confocal stack, taken at the levels indicated by vertical and horizontal blue lines that demonstrate overlapping nestin immunoreactivity and cyclin D2 mRNA signals within the whole cell body. Blue shows DAPI staining revealing the cell nucleus. Bar, 5 μm.
Mentions: We have also investigated the effect of cyclin D2 mutation on the overall brain structure. We have found that the mutant brain is smaller by ∼25%, whereas the weight of the whole mice was lower by no more than 10%, when comparing the D2 KO and WT animals (Fig. 3). These size reductions are already evident in the brains of 2-wk-old mice (unpublished data). The overall brain structure of the D2 mutants appeared close to normal, although such brain regions as hippocampus, occipital cortex, cerebellum, and OB in particular were significantly smaller in mutants than in the WT mice (Fig. 3), whereas the lateral ventricles were expanded (Fig. 3, d and h). Notably, this phenotype is strikingly reminiscent of the effects of the orphan nuclear receptor TLX deficiency that is also lacking adult neurogenesis in the brain (Shi et al., 2004). In OB, the size reduction did associate with a well-defined and prominent abnormality in anatomic structure. As evidenced by Nissl-stained preparations (Fig. 3, b, c, f, and g), there was a striking decrease in cell density in the internal granular layer, and, to a lesser extent, a decrease in number of periglomerular granule cells. In the former layer, the characteristic striated aggregations of granule interneurons were clearly disrupted. Other neuronal populations, including mitral cells, appeared not to be disturbed. The abnormalities in OB structure that are evident in adult mice are also present at P5 (unpublished data). However, hippocampal DG of 5-d-old mice was not strikingly different between WT and D2 KO with plentiful neurogenesis also in the latter (Fig. 4, b and d).

Bottom Line: In contrast, genetic ablation of cyclin D1 does not affect adult neurogenesis.In contrast, all three cyclin D mRNAs are present in the cultures derived from 5-day-old hippocampi, when developmental neurogenesis in the dentate gyrus takes place.Thus, our results reveal the existence of molecular mechanisms discriminating adult versus developmental neurogeneses.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Neurobiology, Nencki Institute, 02-093 Warsaw, Poland.

ABSTRACT
Adult neurogenesis (i.e., proliferation and differentiation of neuronal precursors in the adult brain) is responsible for adding new neurons in the dentate gyrus of the hippocampus and in the olfactory bulb. We describe herein that adult mice mutated in the cell cycle regulatory gene Ccnd2, encoding cyclin D2, lack newly born neurons in both of these brain structures. In contrast, genetic ablation of cyclin D1 does not affect adult neurogenesis. Furthermore, we show that cyclin D2 is the only D-type cyclin (out of D1, D2, and D3) expressed in dividing cells derived from neuronal precursors present in the adult hippocampus. In contrast, all three cyclin D mRNAs are present in the cultures derived from 5-day-old hippocampi, when developmental neurogenesis in the dentate gyrus takes place. Thus, our results reveal the existence of molecular mechanisms discriminating adult versus developmental neurogeneses.

Show MeSH