Region-specific expression of cell cycle inhibitors in the adult brain

Legrier, Marie-Emmanuelle; Ducray, Angélique; Propper, Alain; Kästner, Anne

doi:10.1097/00001756-200110080-00029

Cited by 24 publications

(22 citation statements)

References 24 publications

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“…For example, p15 INK4B has been found in the forebrain, p21 has been found in the cerebellum (30,31), and p27 Kip has been found in the cerebellum and postmitotic cortical neurons (31,32). It is likely that other CDK inhibitors also affect neurogenesis.…”

Section: Discussionmentioning

confidence: 99%

p21 ^Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus

Pechnick

Zonis²,

Wawrowsky³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The subgranular zone (SGZ) of the dentate gyrus of the hippocampus is a brain region where robust neurogenesis continues throughout adulthood. Cyclin-dependent kinases (CDKs) have a primary role in controlling cell division and cellular proliferation. p21 Cip1 (p21) is a CDK inhibitor that restrains cell cycle progression. Confocal microscopy revealed that p21 is abundantly expressed in the nuclei of cells in the SGZ and is colocalized with NeuN, a marker for neurons. Doublecortin (DCX) is a cytoskeletal protein that is primarily expressed by neuroblasts. By using FACS analysis it was found that, among DCX-positive cells, 42.8% stained for p21, indicating that p21 is expressed in neuroblasts and in newly developing neurons. p21-null (p21 ؊/؊ ) mice were examined, and the rate of cellular proliferation, as measured by BrdU incorporation, was increased in the SGZ of p21 ؊/؊ compared with WT mice. In addition, the levels of both DCX and NeuN protein were increased in p21 ؊/؊ mice, further demonstrating increased hippocampal neuron proliferation. Chronic treatment with the tricyclic antidepressant imipramine (10 mg/kg per day i.p. for 21 days) markedly decreased hippocampal p21 mRNA and protein levels, produced antidepressant-like behavioral changes in the forced swim test, and stimulated neurogenesis in the hippocampus. These results suggest that p21 restrains neurogenesis in the SGZ and imipramine-induced stimulation of neurogenesis might be a consequence of decreased p21 expression and the subsequent release of neuronal progenitor cells from the blockade of proliferation. Because many antidepressants stimulate neurogenesis, it is possible that their shared common mechanism of action is suppression of p21.antidepressant ͉ neurogenesis ͉ depression ͉ cyclin-dependent kinase inhibitor I n the central nervous system, developing neurons are derived from quiescent multipotent or neural stem cells and progenitors (1). In the hippocampus, the neural progenitor cells are located in the subgranular zone (SGZ) of the dentate gyrus, at the border between the hilus and the granular cell layer (GCL) (2, 3). Newborn cells proliferate in SGZ, migrate into the GCL, develop the morphological and functional properties of granule cell neurons, and become integrated into existing neuronal circuitry (4). This suggests an important role of intrinsic stimulatory and inhibitory factors in the regulation of proliferation of neuronal precursor cells.In mammalian cells, the control of cellular proliferation primarily is achieved in the G 1 phase of the cell cycle. Cyclindependent kinases (CDKs) tightly control the cell cycle process. Cell cycle progression is negatively regulated by two families of CDK inhibitors: Ink4/ARF type (p16, p15, p18, and p19) and Cip/Kip type (p21, p27, and p57). p21 Cip1 (p21) acts in the G 1 phase of the cell cycle and delays or blocks the progression of the cell into the S phase (5). p21 maintains cell quiescence, and chronic activation of p21 can drive the cell into irreversible cell growth arrest and senescen...

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Section: Discussionmentioning

confidence: 99%

p21 ^Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus

Pechnick

Zonis²,

Wawrowsky³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…In post-mitotic, terminally differentiated neurons, it is likely that cell cycle activity is arrested by the increased expression of Cdk inhibitors. Numerous cell cycle inhibitors are expressed in the brain either in a ubiquitous fashion (e.g., p19 Ink4d ) or in specific regions: p15 Ink4d in the forebrain; p21 Cip1 in the cerebellum 53 and p27 Kip1 in the cerebellum and cortical postmitotic neurons. 53,54 In animals derived from backcrosses between p27 Kip1 -null and p19 Ink4d -null mice, a subpopulation of neurons showed increased proliferation in the brain, indicating that these two Cdk inhibitors cooperate to maintain differentiated neurons in a quiescent but potentially reversible state.…”

Section: Cell Cycle Related Proteins In Adult Brainmentioning

confidence: 99%

Antidepressants and Cdk inhibitors: Releasing the brake on neurogenesis?

Chesnokova¹,

Pechnick²

2008

Cell Cycle

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“…Previous studies have suggested that p21 might participate in the establishment of the postmitotic phenotype of neurons (Erhardt and Pittman, 1998;Legrier et al, 2001). Therefore, we examined by immunofluorescence the expression of p21 in Pax6-expressing cells [ The tumor-suppressor p53 gene is involved in cell cycle regulation and differentiation in several biological systems.…”

Section: Pax6 Induces a Postmitotic Phenotypementioning

confidence: 99%

Pax6-induced alteration of cell fate: Shape changes, expression of neuronal α tubulin, postmitotic phenotype, and cell migration

Cartier¹,

Laforge²,

Féki³

et al. 2006

J. Neurobiol.

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The transcription factor Pax6 plays an important role in the development of the central nervous system. To understand its mechanism of action, we transduced HeLa cells with a Pax6-expressing lentiviral vector. Upon transduction, HeLa cells markedly changed shape and formed neuritelike extensions. Pax6-transduced HeLa cells expressed high levels of neuronal alpha3 tubulin, demonstrating a partial transdifferentiation towards a neuronal phenotype. Neurons are postmitotic cells. Pax6-transduced HeLa cells became postmitotic through mechanisms involving up-regulation of p53 and cyclin-dependent kinase inhibitor p21. One of the most striking effects of Pax6 was observed by time-lapse videomicroscopy: cells started to dissociate from cell clusters and displayed intense migratory activity. Migration was accompanied by dynamic and reversible shape changes. Our results identified three elements of Pax6 action: (i) expression of neuron-specific genes; (ii) establishment of a postmitotic phenotype; and (iii) involvement in the regulation of cell shape and cell migration.

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Region-specific expression of cell cycle inhibitors in the adult brain

Cited by 24 publications

References 24 publications

p21 ^Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus

p21 ^Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus

Antidepressants and Cdk inhibitors: Releasing the brake on neurogenesis?

Pax6-induced alteration of cell fate: Shape changes, expression of neuronal α tubulin, postmitotic phenotype, and cell migration

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Region-specific expression of cell cycle inhibitors in the adult brain

Cited by 24 publications

References 24 publications

p21 Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus

p21 Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus

Antidepressants and Cdk inhibitors: Releasing the brake on neurogenesis?

Pax6-induced alteration of cell fate: Shape changes, expression of neuronal α tubulin, postmitotic phenotype, and cell migration

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p21 ^Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus

p21 ^Cip1 restricts neuronal proliferation in the subgranular zone of the dentate gyrus of the hippocampus