In mammals, 24 hours rhythms are organized as a biochemical network of molecular clocks that are operative in all tissues, with the master clock residing in the hypothalamic suprachiasmatic nucleus (SCN). The core pacemakers of these clocks consist of auto-regulatory transcriptional/post-transcriptional feedback loops. Several lines of evidence suggest the existence of a crosstalk between molecules that are responsible for the generation of circadian rhythms and molecules that control the cell cycle progression. In addition, highly specialized cell cycle checkpoints involved in DNA repair after damage seem also, at least in part, mediated by clock proteins. Recent studies have also highlighted a putative connection between clock protein dysfunction and cancer progression. This review discusses the intimate relation that exists between cell cycle progression and components of the circadian machinery.

Background: Newborn granule neurons are generated from proliferating neural stem/progenitor cells and integrated into mature synaptic networks in the adult dentate gyrus of the hippocampus. Since light/dark variations of the mitotic index and DNA synthesis occur in many tissues, we wanted to unravel the role of the clock-controlled Period2 gene (mPer2) in timing cell cycle kinetics and neurogenesis in the adult DG.

The presence of neurogenic precursors in the adult mammalian brain is now widely accepted, but the mechanisms coupling their proliferation with the onset of neuronal differentiation remain unknown. Here, we unravel the major contribution of the G 1 regulator cyclin-dependent kinase 6 (Cdk6) to adult neurogenesis. We found that Cdk6 was essential for cell proliferation within the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles. Specifically, Cdk6 deficiency prevents the expansion of neuronally committed precursors by lengthening G 1 phase duration, reducing concomitantly the production of newborn neurons. Altogether, our data support G 1 length as an essential regulator of the switch between proliferation and neuronal differentiation in the adult brain and Cdk6 as one intrinsic key molecular regulator of this process. STEM CELLS 2011;29:713-724 Disclosure of potential conflicts of interest is found at the end of this article.

The adult brain most probably reaches its highest degree of plasticity with the lifelong generation and integration of new neurons in the hippocampus and olfactory system. Neural precursor cells (NPCs) residing both in the subgranular zone of the dentate gyrus and in the subventricular zone of the lateral ventricles continuously generate neurons that populate the dentate gyrus and the olfactory bulb, respectively. The regulation of NPC proliferation in the adult brain has been widely investigated in the past few years. Yet, the intrinsic cell cycle machinery underlying NPC proliferation remains largely unexplored. In this review, we discuss the cell cycle components that are involved in the regulation of NPC proliferation in both neurogenic areas of the adult brain.

For a long time it was believed that the adult mammalian brain was completely unable to regenerate after insults. However, recent advances in the field of stem cell biology, including the identification of adult neural stem cells (NSCs) and evidence regarding a continuous production of neurons throughout life in the dentate gyrus (DG) and the subventricular zone of the lateral ventricles (SVZ), have provided new hopes for the development of novel therapeutic strategies to induce regeneration in the damaged brain. Moreover, proofs have accumulated this last decade that endogenous stem/progenitor cells of the adult brain have an intrinsic capacity to respond to brain disorders. Here, we first briefly summarize our current knowledge related to adult neurogenesis before focusing on the behaviour of adult neural stem/progenitors cells following stroke and seizure, and describe some of the molecular cues involved in the response of these cells to injury. In the second part, we outline the consequences of three main neurodegenerative disorders on adult neurogenesis and we discuss the potential therapeutic implication of adult neural stem/progenitors cells during the course of these diseases.

In white matter disorders such as leukodystrophies (LD), periventricular leucomalacia (PVL), or multiple sclerosis (MS), the hypomyelination or the remyelination failure by oligodendrocyte progenitor cells involves errors in the sequence of events that normally occur during development when progenitors proliferate, migrate through the white matter, contact the axon, and differentiate into myelin-forming oligodendrocytes. Multiple mechanisms underlie the eventual progressive deterioration that typifies the natural history of developmental demyelination in LD and PVL and of adult-onset demyelination in MS. Over the past few years, pathophysiological studies have mostly focused on seeking abnormalities that impede oligodendroglial maturation at the level of migration, myelination, and survival. In contrast, there has been a strikingly lower interest for early proliferative and differentiation events that are likely to be equally critical for white matter development and myelin repair. This review highlights the Yin and Yang principles of interactions between intrinsic factors that coordinately regulate progenitor cell division and the onset of differentiation, i.e. the initial steps of oligodendrocyte lineage progression that are obviously crucial in health and diseases.

Granule neurons of the dentate gyrus (DG) of the hippocampus undergo continuous renewal throughout life. Among cell cycle regulators, cyclin-dependent kinase 2 (Cdk2) is considered as a major regulator of S-phase entry. We used Cdk2-deficient mice to decipher the requirement of Cdk2 for the generation of new neurons in the adult hippocampus. The quantification of cell cycle markers first revealed that the lack of Cdk2 activity does not influence spontaneous or seizure-induced proliferation of neural progenitor cells (NPC) in the adult DG. Using bromodeoxyuridine incorporation assays, we showed that the number of mature newborn granule neurons generated de novo was similar in both wild-type (WT) and Cdk2-deficient adult mice. Moreover, the apparent lack of cell output reduction in Cdk2 -/-mice DG did not result from a reduction in apoptosis of newborn granule cells as analyzed by TUNEL assays. Our results therefore suggest that Cdk2 is dispensable for NPC proliferation, differentiation and survival of adult-born DG granule neurons in vivo. These data emphasize that functional redundancies between Cdks also occur in the adult brain at the level of neural progenitor cell cycle regulation during hippocampal neurogenesis.

Neural stem cells give rise to granule dentate neurons throughout life in the hippocampus. Upon activation, these stem cells generate fast proliferating progenitors that complete several rounds of divisions before differentiating into neurons. Although the mechanisms regulating the activation of stem cells have been intensively studied, little attention has been given so far to the intrinsic machinery allowing the expansion of the progenitor pool. The cell cycle protein Cdk6 positively regulates the proliferation of hippocampal progenitors, but the mechanism involved remains elusive. Whereas Cdk6 functions primarily as a cell cycle kinase, it can also act as transcriptional regulator in cancer cells and hematopoietic stem cells. Using mouse genetics, we show here that the function of Cdk6 in hippocampal neurogenesis relies specifically on its kinase activity. The present study also reveals a specific regulatory mechanism for Cdk6 in hippocampal progenitors. In contrast to the classical model of the cell cycle, we observe that the Cip/Kip family member p27, rather than the Ink4 family, negatively regulates Cdk6 in the adult hippocampus. Altogether, our data uncover a unique, cell type-specific regulatory mechanism controlling the expansion of hippocampal progenitors, where Cdk6 kinase activity is modulated by p27.