Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases

Zindy, Frédérique; Cunningham, Justine J.; Sherr, Charles J.; Jogal, Sachin; Smeyne, Richard J.; Roussel, Martine F.

doi:10.1073/pnas.96.23.13462

Cited by 158 publications

(131 citation statements)

References 35 publications

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“…4 I,L, compare arrows, asterisks). Previous studies have shown that null mutation of the G 1 -phase CDK inhibitors p27Kip1 and p19INK4d cause postnatal neuronal proliferation in these mice (Zindy et al, 1999). Thus, the observed reduction of p27Kip1 and P16INK4 may promote the G 1 /S-phase transition after cerebral hypoxia-ischemia.…”

Section: Apoptotic Neurons Display Hallmarks Of the G 1 /S-phase Cellmentioning

confidence: 75%

Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain

et al. 2004

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Recent studies suggest that postmitotic neurons can reenter the cell cycle as a prelude to apoptosis after brain injury. However, most dying neurons do not pass the G 1 /S-phase checkpoint to resume DNA synthesis. The specific factors that trigger abortive DNA synthesis are not characterized. Here we show that the combination of hypoxia and ischemia induces adult rodent neurons to resume DNA synthesis as indicated by incorporation of bromodeoxyuridine (BrdU) and expression of G 1 /S-phase cell cycle transition markers. After hypoxia-ischemia, the majority of BrdU-and neuronal nuclei (NeuN)-immunoreactive cells are also terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL)-stained, suggesting that they undergo apoptosis. BrdU ϩ neurons, labeled shortly after hypoxia-ischemia, persist for Ͼ5 d but eventually disappear by 28 d. Before disappearing, these BrdU ϩ /NeuN ϩ / TUNEL ϩ neurons express the proliferating cell marker Ki67, lose the G 1 -phase cyclin-dependent kinase (CDK) inhibitors p16INK4 and p27Kip1 and show induction of the late G 1 /S-phase CDK2 activity and phosphorylation of the retinoblastoma protein. This contrasts to kainic acid excitotoxicity and traumatic brain injury, which produce TUNEL-positive neurons without evidence of DNA synthesis or G 1 /S-phase cell cycle transition. These findings suggest that hypoxia-ischemia triggers neurons to reenter the cell cycle and resume apoptosis-associated DNA synthesis in brain. Our data also suggest that the demonstration of neurogenesis after brain injury requires not only BrdU uptake and mature neuronal markers but also evidence showing absence of apoptotic markers. Manipulating the aberrant apoptosis-associated DNA synthesis that occurs with hypoxia-ischemia and perhaps neurodegenerative diseases could promote neuronal survival and neurogenesis.

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Section: Apoptotic Neurons Display Hallmarks Of the G 1 /S-phase Cellmentioning

confidence: 75%

Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain

et al. 2004

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“…It is likely that other CDK inhibitors also affect neurogenesis. Double knockout animals obtained from crossing p19-null and p27-null mice exhibit increased neuronal proliferation in all parts of the brain (33). Given the capacity of p21 to restrain the cell cycle, its localization in the SGZ, and its confinement to DCX-positive cells, p21 might play an important and unique role in regulating neuronal proliferation in the hippocampus of adult mice.…”

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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“…Indeed, double knockout mice provided evidence that collaboration between p18 INK4C and p19 INK4D is necessary to regulate spermatogenesis, notably during the normal meiotic maturation of spermatocytes. 19 In addition, p19 INK4D in cooperation with p27 KIP1 is essential to the maintenance of the terminally differentiated postmitotic neurons 20,21 and sensory hair cells 22 in postnatal mice. Finally, in mice lacking Msx1, significantly elevated p19 INK4D expression was linked to a reduction in cranial neural crest cell proliferation in dental mesenchyme, suggesting an important role of p19 INK4D during tooth morphogenesis.…”

Section: Introductionmentioning

confidence: 99%

P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1

Gilles

Guièze

Bluteau

et al. 2008

Blood

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The molecular mechanisms that regulate megakaryocyte (MK) ploidization are poorly understood. Using MK differentiation from primary human CD34 ؉ cells, we observed that p19 INK4D expression was increased both at the mRNA and protein levels during ploidization. p19 INK4D knockdown led to a moderate increase (31.7% ؎ 5%) in the mean ploidy of MKs suggesting a role of p19 INK4D in the endomitotic arrest. This increase in ploidy was associated with a decrease in the more mature MK population (CD41 high CD42 high ) at day 9 of culture, which was related to a delay in differentiation. Inversely, p19 INK4D Until now, the best-studied model of polyploidization concerns megakaryocytes (MKs) in which after several replicative rounds, the process of classic mitosis is replaced by an endomitotic process. MK endomitosis is very similar to mitosis, but MKs skip anaphase B, telophase, and cytokinesis giving rise to a polyploid cell with a single polylobulated nucleus. 1,2 Although polyploidization is a part of the MK differentiation program, terminal differentiation that is associated with an increased platelet protein synthesis and the development of specific organelles requires an arrest of the cell cycle. Both the mitotic and endomitotic processes require an amplification of the DNA content. However, while mitosis leads to an increase in cell number, polyploidization results in an increase in the cell size and protein mass. In the case of MK, the platelet precursor, polyploidization increases platelet production.DNA replication is a regulated mechanism that depends on a well-organized network of the cyclin-dependent kinases (CDKs) and cyclin-dependent inhibitors (CDKIs) of the cell cycle. Progression through G1 to S phase of cell cycle in mammalian cells requires the activity of G1-cyclins (D and E) associated with their catalytic subunits (CDK4 and CDK6). The mitogen-stimulated cyclin D and CDK4/6 complexes phosphorylate the retinoblastoma protein (Rb) allowing its dissociation from E2Fs transcription factors. Activated E2Fs then regulate the expression of genes necessary for DNA synthesis during the S phase of cell cycle. Cells exit cell cycle and accumulate in a quiescent G 0 /G 1 state either in the absence of mitogenic stimuli when the cyclin D-dependent activity is lost or after CDK4/6 inhibition. CDKs are regulated by inhibitory phosphorylations mediated by the WEE1 and MYT1 kinases 3 or by induction of specific inhibitors from the INK4 and CIP/KIP families. Till now, 4 members of the INK4 family (p19 INK4D , p18 INK4C , p16 INK4A , and p15 INK4B ) are described to specifically block the activity of CDK4/6 either by forming inactive ternary INK4-CDK4/6-cyclin D or binary INK4-CDK4/6 complexes. 4 The members of the CIP/KIP family (p21 CIP1/WAF1 , p27 KIP1 , and p57 KIP2 ) inhibit cyclin A-or cyclin E-associated CDK2 activity, but stabilize cyclin D-associated CDK4/6 activity. 5,6 In MKs, a high level of 2 CIP/KIP family members, p21 CIP1 and p27 KIP1 ,7,8 and 1 member of the INK4 family, p16 INK4A , 7 was detected...

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Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases

Cited by 158 publications

References 35 publications

Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain

Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain

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

P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1

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Postnatal neuronal proliferation in mice lacking Ink4d and Kip1 inhibitors of cyclin-dependent kinases

Cited by 158 publications

References 35 publications

Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain

Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain

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

P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1

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