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

Abstract

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...

Antidepressants and Cdk inhibitors: Releasing the brake on neurogenesis?

“…This imipramine-induced increase in the number of SGZ neurons was associated with markedly decreased hippocampal p21 Cip1 mRNA and protein levels, concordant with an increased number of mature neurons expressing NeuN. 67 These results suggest that p21 Cip1 restrains neurogenesis in the SGZ, and the imipramineinduced stimulation of neurogenesis might be a consequence of decreased p21 Cip1 expression and the subsequent release of neuronal progenitor cells from the blockade of proliferation. These data were the first to show that proteins involved in the regulation of the cell cycle are a possible mechanistic link between neurogenesis and action of antidepressants.…”

“…66 Loss of p27 Kip1 has no effect on the number of NSC, but selectively increases the number of transit-amplifying progenitors concomitantly with a reduction in the number of neuroblasts in the SVZ. Recently, we demonstrated the abundant expression of intranuclear p21 Cip1 in the SGZ, where it is colocalized with NeuN, a marker for neurons 67 (Fig. 1).…”

“…93,94 We found that treatment with antidepressant for three weeks suppresses murine SGZ p21 Cip1 expression with a subsequent increase in hippocampal neurogenesis. 67 Therefore it is conceivable that suppression of p21 Cip1 by longer treatment could result in eventual and premature exhaustion of neuronal precursors as it was observed in aging p21 Cip1 -null mice. 93 If this is the case, then in some instances it could lead to the loss of therapeutic efficacy, or the development of treatment refractory depression, and this appears to be true.…”

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

“…(van Os et al, 2007) Increased neurogenesis and neuronal regeneration, exhaustion of neuronal stem cells during aging. (Pechnick et al, 2008;Kippin et al, 2005;Qiu et al, 2004) Elongated lifespan. Improved maintenance and function of HSCs.…”

An essential role for Ink4 and Cip/Kip cell-cycle inhibitors in preventing replicative stress

“…[36][37][38] p21 Cip1 , on the other hand, can restrain neurogenesis in the subgranular zone of the dentate gyrus. 39 Hyperactivation of Cdk4 has been related to defects in neurogenesis and promotion of basal progenitor proliferation. 25 Homozygous deletion of the human locus encoding p16 Ink4a -p19 ARF -p15 Ink4b , often accompanied by deletion or mutation in p18 Ink4c , is among the most common genetic alterations in glioblastoma multiforme.…”