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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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Adult hippocampus and OB of D2 KO mice deficient in neurogenesis. (a–d) Extensive labeling in hippocampal DG in controls: wild-type (WT) from D1 KO line (c), WT from D2 KO line (d) and D1 KO mouse (a). Lack of labeling in DG of D2 KO hippocampus (b). (e–h) Similar phenomenon in OB. (i and j) Colocalization (arrows) of BrdU (red) and NeuN (green) in WT hippocampus. (k and l) BrdU-positive nuclei in D2 KO hippocampus never colocalize with NeuN. (o) Similar colocalization (arrowheads indicating green rings) of BrdU (red) and Tuj-1 (green) with no colocalization in D2 KO (p). (m and n) Colabeling of BrdU with glial fibrillary acidic protein (GFAP, green) in D2 KO hippocampus. Confocal images: single-plane (i–l and o and p) and composed (m and n). Bars: (a–h) 200 μm; (i–l, m and n, and o and p) 20 μm.
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fig1: Adult hippocampus and OB of D2 KO mice deficient in neurogenesis. (a–d) Extensive labeling in hippocampal DG in controls: wild-type (WT) from D1 KO line (c), WT from D2 KO line (d) and D1 KO mouse (a). Lack of labeling in DG of D2 KO hippocampus (b). (e–h) Similar phenomenon in OB. (i and j) Colocalization (arrows) of BrdU (red) and NeuN (green) in WT hippocampus. (k and l) BrdU-positive nuclei in D2 KO hippocampus never colocalize with NeuN. (o) Similar colocalization (arrowheads indicating green rings) of BrdU (red) and Tuj-1 (green) with no colocalization in D2 KO (p). (m and n) Colabeling of BrdU with glial fibrillary acidic protein (GFAP, green) in D2 KO hippocampus. Confocal images: single-plane (i–l and o and p) and composed (m and n). Bars: (a–h) 200 μm; (i–l, m and n, and o and p) 20 μm.

Mentions: Most often the neurogenesis is revealed by means of intense incorporation of DNA precursors, e.g., BrdU into neuronal nuclei that occurs during the S phase of the cell cycle (Takahashi et al., 1992; Luskin, 1993; Kuhn et al., 1996). In the first series of experiments, we investigated BrdU incorporation 1 d after the last of four i.p. injections. Mice with cyclin D2 gene disrupted through homologous recombination (D2 KO; Sicinski et al., 1996) were virtually deprived of BrdU incorporation in the hippocampus and OB. In contrast, robust labeling of these brain structures could be observed in the brains of their wild-type (WT) littermates (Fig. 1, a–h). In addition, mice deficient in cyclin D1 (Sicinski et al., 1995) displayed BrdU incorporation similar to their control WT littermates.


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)

Adult hippocampus and OB of D2 KO mice deficient in neurogenesis. (a–d) Extensive labeling in hippocampal DG in controls: wild-type (WT) from D1 KO line (c), WT from D2 KO line (d) and D1 KO mouse (a). Lack of labeling in DG of D2 KO hippocampus (b). (e–h) Similar phenomenon in OB. (i and j) Colocalization (arrows) of BrdU (red) and NeuN (green) in WT hippocampus. (k and l) BrdU-positive nuclei in D2 KO hippocampus never colocalize with NeuN. (o) Similar colocalization (arrowheads indicating green rings) of BrdU (red) and Tuj-1 (green) with no colocalization in D2 KO (p). (m and n) Colabeling of BrdU with glial fibrillary acidic protein (GFAP, green) in D2 KO hippocampus. Confocal images: single-plane (i–l and o and p) and composed (m and n). Bars: (a–h) 200 μm; (i–l, m and n, and o and p) 20 μm.
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Related In: Results  -  Collection

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fig1: Adult hippocampus and OB of D2 KO mice deficient in neurogenesis. (a–d) Extensive labeling in hippocampal DG in controls: wild-type (WT) from D1 KO line (c), WT from D2 KO line (d) and D1 KO mouse (a). Lack of labeling in DG of D2 KO hippocampus (b). (e–h) Similar phenomenon in OB. (i and j) Colocalization (arrows) of BrdU (red) and NeuN (green) in WT hippocampus. (k and l) BrdU-positive nuclei in D2 KO hippocampus never colocalize with NeuN. (o) Similar colocalization (arrowheads indicating green rings) of BrdU (red) and Tuj-1 (green) with no colocalization in D2 KO (p). (m and n) Colabeling of BrdU with glial fibrillary acidic protein (GFAP, green) in D2 KO hippocampus. Confocal images: single-plane (i–l and o and p) and composed (m and n). Bars: (a–h) 200 μm; (i–l, m and n, and o and p) 20 μm.
Mentions: Most often the neurogenesis is revealed by means of intense incorporation of DNA precursors, e.g., BrdU into neuronal nuclei that occurs during the S phase of the cell cycle (Takahashi et al., 1992; Luskin, 1993; Kuhn et al., 1996). In the first series of experiments, we investigated BrdU incorporation 1 d after the last of four i.p. injections. Mice with cyclin D2 gene disrupted through homologous recombination (D2 KO; Sicinski et al., 1996) were virtually deprived of BrdU incorporation in the hippocampus and OB. In contrast, robust labeling of these brain structures could be observed in the brains of their wild-type (WT) littermates (Fig. 1, a–h). In addition, mice deficient in cyclin D1 (Sicinski et al., 1995) displayed BrdU incorporation similar to their control WT littermates.

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