Brain Plasticity 1 (2015) 41–54 41 DOI 10.3233/BPL-150013 IOS Press Review Control of the Cell Cycle in Adult Neurogenesis and its Relation with Physical Exercise Stefano Farioli-Vecchioli∗ and Felice Tirone∗ Institute of Cell Biology and Neurobiology, National Research Council, Fondazione S.Lucia, Rome, Italy Abstract. In the adult brain the neurogenesis is mainly restricted to two neurogenic regions: newly generated neurons arise at the subventricular zone (SVZ) of the lateral ventricle and at the subgranular zone of the hippocampal subregion named the dentate gyrus. The hippocampus is involved in learning and memory paradigms and the generation of new hippocampal neurons has been hypothesized to be a pivotal form of plasticity involved in the process. Moreover the dysregulation of hippocampal adult neurogenesis has been recognized and could anticipate several varieties of brain disease such as Alzheimer disease, epilepsy and depression. Over the last few decades numerous intrinsic, epigenetic and environmental factors have been revealed to deeply influence the process of adult neurogenesis, although the underlying mechanisms remain largely unknown. Growing evidence indicates that physical exercise represents one of the main extrinsic factor able to profoundly increase hippocampal adult neurogenesis, by altering neurochemistry and function of newly generated neurons. The present review surveys how neurogenesis can be modulated by cell cycle kinetics and highlights the putative role of the cell cycle length as a key component of the beneficial effect of running for hippocampal adult neurogenesis, both in physiological conditions and in the presence of defective neurogenesis. Keywords: Cell cycle, self-renewal, adult neurogenesis, physical exercise, neural stem cell niche INTRODUCTION lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus of the hippocampal formation [1]. Since 1962 when Altman suggested the presence Newborn neurons in the SVZ migrate through the ros- of newly generated neurons in the adult brain, huge tral migratory stream where they become granule and progress has been made in understanding the cellular periglomerular neurons in the olfactory bulb. Cells and molecular processes that govern the prolifera- born in the adult SGZ migrate into the deep layer of tion, differentiation and integration of new neurons the dentate gyrus and fully differentiate into excita- in the preexisting memory circuits. Adult neurogen- tory dentate granule cells [2]. Adult neurogenesis is an esis has been clearly identified and confirmed in two highly dynamic process that can be finely modulated brain regions: the subventricular zone (SVZ) of the both negatively by stress and aging and positively, by means of physical activity, environment enrichment, ∗Correspondence to: Dr. Stefano Farioli-Vecchioli and Felice and learning. Among these factors numerous stud- Tirone, Institute of Cell Biology and Neurobiology, Consiglio ies have pointed out that voluntary physical activity Nazionale delle Ricerche, Fondazione S.Lucia, via del Fosso di represent the most potent inducer of adult neurogen- Fiorano 64, 00143 Rome, Italy. Tel.: +39 06 50170 3187; Fax: +39 06 50170 3313; E-mail: [email protected] and Tel.: +39 06 esis [3–5]. However the running-induced increase of 50170 3184; Fax: +39 06 50170 3313; E-mail: [email protected]. proliferation is region-specific, occurring exclusively ISSN 2213-6304/15/$35.00 © 2015 – IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License. 42 S. Farioli-Vecchioli and F. Tirone / Cell Cycle, Neurogenesis and Running in the hippocampus while it does not enhance SVZ a broader range of Cdk inhibitory activity compared neurogenesis [6]. to the Ink4 inhibitors and contain characteristic motifs In this review we first summarize the recent dis- that enable them to interfere with cyclin E/CDK2 or coveries describing the cell cycle components and cyclin A/CDK2 to block or slow down the cell cycle mechanisms which underlie proliferation of the neural progression [18, 19]. precursors cells in the adult neurogenic niches. Then we focus on new data regarding changes in the cell cycle kinetics and lengthening observed in the two neu- ROLE OF THE CELL CYCLE MACHINERY rogenic niches. Finally we will analyze how the length IN ADULT NEUROGENESIS of the cell cycle might have a major role in triggering the increased proliferation following running. The finding that the production of new neurons continues throughout life in the adult mammalian brain has generated enormous interest and substantial PROTEINS AND REGULATORS OF THE advances in the field of neuroscience. During the adult CELL CYCLE neurogenesis occurring in SVZ and dentate gyrus neuroblasts are continuously produced and migrate The cell cycle is a process that leads to the duplica- to reach their targeted circuits where they fully tion of the cell into two daughter cells. This mechanism differentiate into mature neurons and integrate into the consist of a series of events starting from a quiescent preexisting network [20]. Despite the common origin state (G0) followed by the entry into the first phase from neural stem cells, the neuroblasts originated in (G1) during which the cell prepares for DNA replica- SVZ and in the dentate gyrus display highly different tion (S phase). Later the cell enters in a second gap in proliferative properties and differentiation fate, which which it continues to grow (G2), followed by the mito- in turn give rise to mature neurons with profoundly sis (M). This complex mechanism is finely orchestrated different morphological and electrophysiological by the highly coordinated action of two main classes characteristics (see below). Consequently, the cell of molecules: the cyclin-dependent kinases (Cdks) and cycle machinery in the two different adult neurogenic their regulatory partners, i.e., the cyclins [7]. In the G1 niches presents a substantial diversity as regards the phase cyclin D forms a complex with Cdk4/6 to phos- molecular mediators involved and replicative kinetics phorylate the retinoblastoma protein pRB, inducing the of the proliferating cell types. E2f transcription factor to trigger the expression of sev- In recent years, numerous studies have revealed an eral genes involved in the cell cycle progression [8, 9]. important role of the molecules of the cell cycle in the Another complex, Cdk2-cyclinE, further phosphory- regulation of quiescence and expansion of stem cells lates Rb activating the transcription of genes essential and of differentiation of neural progenitors in the adult for the DNA replication phase entry [10, 11]. Later, the neurogenic niches [21, 22]. We should consider that interaction between Cdk2 and cyclin A regulates S/G2 the amount of new neurons generated depends on three transition [12]. Finally, Cdk1 and cyclin B complex components: i) the division mode; an asymmetric (neu- (being also denominated “mitosis promoting factor”) rogenic) division of a neural stem cell maintains the controls the onset of mitosis and regulates the struc- original pool, by generating one replica of the mother tural steps during the cell division [13]. The cell cycle cell and one differentiating cell, while a symmetric is negatively regulated at any specific checkpoint by neurogenic division generates two new neurons at the two major classes of non enzymatic cyclin-dependent expense of the pool of mother cells; ii) the length of kinase inhibitors (CDKIs) that directly interact with cell cycle; iii) the fraction of cells that exit the cycle already formed cyclin-CDK complexes: the INK4 and enters quiescence or differentiates; this key deci- and the CDK-inhibitory protein (CIP)/kinase-inhibitor sion occurs at the G1 phase [23]. A decrease of the protein (KIP) families [14, 15]. The CIP/KIP inhibitors cell cycle length, in stem/progenitor cells, by accel- have a broad CDK preference and have been impli- erating the division rate, may be a primary inducer cated in cell cycle withdrawal and quiescence [16]. The of the generation of a greater number of neurons in INK4 family includes four proteins (p16Ink4a, p15Ink4b, consequence of an expansion of the progenitor cells, p18Ink4c and p19Ink4d) that play a pivotal role in pre- but it requires to be accompanied by the appropriate venting the formation of cyclin/Cdk4-6 complexes mode of division leading to exit from cell cycle and to [17]. The CIP/KIP family comprises three proteins in differentiation (e.g., subsequent rounds of symmetric mammals (p21Cip1, p27Kip1 and p57Kip2) which have proliferative and then neurogenic divisions). S. Farioli-Vecchioli and F. Tirone / Cell Cycle, Neurogenesis and Running 43 CELL CYCLE REGULATION IN THE tissues where, unlike the other CDKs, is predominantly ADULT DENTATE GYRUS activated in post-mitotic cells, either in embryo or in the neurogenic regions of the adult brain. Cdk5 is The adult neurogenesis in adult dentate gyrus has involved in various cellular events not directly related been divided into different developmental stages in to cell cycle, such as regulation of several steps in which quiescent neural stem cells enter into the cell neuronal migration and differentiation by controlling cycle(type1NSCs)andgiverisetopostmitoticneurons microtubule and actin cytoskeletal organization in the through three consecutive stages of intermediate pro- cerebellum and neocortex, and regulation of synaptic