Neuronal cell cycle

Last updated April 28, 2024

The Neuronal cell cycle represents the life cycle of the biological cell, its creation, reproduction and eventual death. The process by which cells divide into two daughter cells is called mitosis. Once these cells are formed they enter G1, the phase in which many of the proteins needed to replicate DNA are made. After G1, the cells enter S phase during which the DNA is replicated. After S, the cell will enter G2 where the proteins required for mitosis to occur are synthesized. Unlike most cell types however, neurons are generally considered incapable of proliferating once they are differentiated, as they are in the adult nervous system. Nevertheless, it remains plausible that neurons may re-enter the cell cycle under certain circumstances. Sympathetic and cortical neurons, for example, try to reactivate the cell cycle when subjected to acute insults such as DNA damage, oxidative stress, and excitotoxicity. This process is referred to as “abortive cell cycle re-entry” because the cells usually die in the G1/S checkpoint before DNA has been replicated.

Cell cycle regulation

Transitions through the cell cycle from one phase to the next are regulated by cyclins binding their respective cyclin dependent kinases (Cdks) which then activate the kinases (Fisher, 2012). During G1, cyclin D is synthesized and binds to Cdk4/6, which in turn phosphorylates retinoblastoma (Rb) protein and induces the release of the transcription factor E2F1 which is necessary for DNA replication (Liu et al., 1998). The G1/S transition is regulated by cyclin E binding to Cdk2 which phosphorylates Rb as well (Merrick and Fisher, 2011). S phase is then driven by the binding of cyclin A with Cdk2. In late S phase, cyclin A binds with Cdk1 to promote late replication origins and also initiates the condensation of the chromatin in the late G2 phase. The G2/M phase transition is regulated by the formation of the Cdk1/cyclin B complex.

Inhibition through the cell cycle is maintained by cyclin-dependent kinase inhibitors (CKIs) of the Ink and Cip/Kip families which inhibit the cyclin/CDK complex. CDK4/6 is inhibited by p15Ink4b, p16Ink4a, p18Ink4c, and p19Ink4d. These inhibitors prevent the binding of CDK4/6 with cyclin D (Cánepa et al., 2007). The Cip/Kip families (p21Cip1, p27Kip1, and p57Kip2) also bind to cyclin/CDK complexes and prohibit advancement through the cell cycle. The cell cycle uses these CDKs and CKIs to regulate the cell cycle through checkpoints. These checkpoints ensure that the cell has completed all of the tasks of the current phase before they can gain entry into the next phase of the cycle. The criteria for the checkpoints are met through a combination of activating and inhibiting cyclin/CDK complexes as the result of different signaling pathways (Besson et al., 2008; Cánepa et al., 2007; Yasutis and Kozminski, 2013). If the criteria are not met, the cell will arrest in the phase prior to the checkpoint until the criteria are met. Progression through a checkpoint without having first met the appropriate criteria can lead to cell death (Fisher, 2012; Williams and Stoeber, 2012).

Abortive cell cycle re-entry

It is believed that neurons are permanently blocked from the cell cycle once they differentiate. As a result, neurons are typically found outside of the cell cycle in a G0 state. It has been found that various genes that encode the G1/S transition, such as D1, Cdk4, Rb proteins, E2Fs, and CKIs, can be detected in different areas of a normal human brain (Frade and Ovejero-Benito, 2015). The presence of these core cell cycle factors can be explained through their role in neuronal migration, maturation, and synaptic plasticity (Christopher L. Frank1 and Li-Huei Tsai1, 2009). However, it is also possible that, under certain conditions, these factors can induce cell cycle re-entry. Under conditions such as DNA damage, oxidative stress, and activity withdrawal these factors have been shown to be upregulated. However the cells usually die in the G1/S checkpoint before DNA has been replicated (Park et al., 1998).

The process by which the cell re-enters the cell cycle and dies is called “abortive cell cycle re-entry” and is characterized by the upregulation of cyclin D-cdk4/6 and downregulation of E2F, followed by cell death (Frade and Ovejero-Benito, 2015). In cerebellar granule cells and cortical neurons, E2F1 can trigger neuronal apoptosis through activation of Bax/caspase-3 and the induction of the Cdk1/FOXO1/Bad pathway (Giovanni et al., 2000). The downregulation of p130/E2F4 (a complex which has been shown to maintain the post mitotic nature of neurons) induces neuronal apoptosis by upregulating B-myb and C-myb (Liu et al., 2005).

Cell cycle re-entry

Tetraploid neurons (neurons with 4C DNA content) are not restricted to retinal neurons, 10% of human cortical neurons have DNA higher than 2C (Frade and Ovejero-Benito, 2015). Typically differentiated neurons that replicate their DNA die. However, this is not always the case as exhibited by sensory and sympathetic neurons, which are able to replicate their DNA without neuronal death (Smith et al., 2000). Neurons that are Rb deficient have also been found to re-enter the cell cycle and survive in a 4C DNA state (Lipinski et al., 2001). Duplication of DNA can lead to neuronal diversification in vertebrates, as seen in observations in the developing chick retina.

These neurons re-enter the cell cycle as they travel to the ganglion cell layer when they are activated by p75NTR. These neurons are unable to enter mitosis and are stuck in a 4C DNA content state. Cell cycle re-entry by p75NTR is not dependent on Cdk4/6 (Morillo et al., 2012) and, therefore, differs from other cell types that re-enter the cell cycle. In retinal ganglion cells, p75NTR is mediated by p38MAPK and then phosphorylates E2F4, before progressing the cell through the cell cycle. Tetraploid neurons in mice are made in a p75NTR dependent manner in cells that contain Rb during their migration to their differentiated neuronal layers (Morillo et al., 2012). It is still unknown why these neurons are able to pass through the G1/S checkpoint and not induce apoptosis through E2F1.

Neurodegenerative diseases

Cell cycle re-entry usually causes apoptosis. However, in some neurodegenerative diseases, re-entry into the cell cycle occurs. The neurons that are able to re-enter the cell cycle are much more likely to undergo apoptosis and lead to the disease phenotypes. In Alzheimer’s disease, affected neurons show signs of DNA replication such as phosphorylated Mcm2 and cell cycle regulators cyclin D, Cdk4, phosphorylated Rb, E2F1, and cyclin E. Not much is currently known about the direct mechanism by which the cell cycle is reactivated, however it is possible that MiR26b may regulate the activation of cell cycle progression by upregulating cyclin E1 and downregulating p27Kip1 (Busser et al., 1998; Yang et al., 2003).

Alzheimer diseased neurons rarely exhibit the ability to enter mitosis and, if they don’t undergo rapid mitosis, can survive for long periods of time in a tetraploid state. These neurons are able to enter the S phase and replicate their DNA, however they become blocked in the G2 state.

In affected and unaffected tetraploid neurons, during development and during the progression of the disease, passing the G2/M checkpoint leads to cell death. This hints that the G2/M checkpoint aids in the survival of tetraploid neurons. This is supported by experiments in which the G2/M checkpoint is removed through addition of brain-derived neurotrophic factor (BDNF) blockers in tetraploid cells that resulted in cell death. BDNF prevents the G2/M transition through its receptor TrkB and their capacity to decrease cyclin B and Cdk1. The mechanism by which neurons undergo apoptosis after the G2/M transition is not yet fully understood, it is known that Cdk1 can activate the pro-apoptotic factor Bad by phosphorylating its Ser128 (Frade, 2000).

Interkinetic nuclear migration

Interkinetic nuclear migration is a feature of developing neuroepithelia and is characterized by the periodic movement of the cell’s nucleus with the progression of the cell cycle. Developing neuroepithelia are tissues composed of neural progenitor cells, each spanning the entire thickness of the epithelium from the ventricular surface to the laminal side. Cell nuclei occupy different positions along the apical–basal axis of the tissue. S phase occurs close to the basal side whereas mitosis exclusively occurs close to ventricular apical side. The nuclei then move to upper regions near the basal side where they proceed through S-phase.

This nuclear movement is repeated at each cell cycle and is maintained by an apical-to-basal migration during G1- phase and a reverse basal-to-apical movement during G2- phase. It was proposed that the INM maximized the amount of mitotic events in the limited space and that, since neuronal progenitors have a basal body, they need to move their nucleus to the apical side in order to assemble the mitotic spindle used in mitosis. It has been reported that the INM is not required for the cell cycle since removing the INM doesn’t change the length of the cell cycle. Interestingly, blocking or delaying the cell cycle results in the arrest or reduction of the INM respectively. Nuclear migration is not necessary for cell cycle regulation, however cell cycle regulators have tight control over the INM (Del Bene, 2011).

Bibliography

Del Bene, F. (2011). Interkinetic nuclear migration: Cell cycle on the move. EMBO J. 30, 1676–1677.
Besson, A., Dowdy, S.F., and Roberts, J.M. (2008). CDK Inhibitors: Cell Cycle Regulators and Beyond. Dev. Cell 14, 159–169.
Busser, J., Geldmacher, D.S., Herrup, K., Hof, P.R., Duff, K., and Davies, P. (1998). Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer’s disease brain. J. Neurosci. 18, 2801–2807.
Cánepa, E.T., Scassa, M.E., Ceruti, J.M., Marazita, M.C., Carcagno, A.L., Sirkin, P.F., and Ogara, M.F. (2007). INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IUBMB Life 59, 419–426.
Christopher L. Frank1 and Li-Huei Tsai1, 2 (2009). Alternative functions of core cell cycle regulators in neuronal migration, neuronal maturation, and synaptic plasticity. NIH Public Access 62, 312–326.
Fisher, R.P. (2012). The CDK network: Linking cycles of cell sdivision and gene expression. Genes and Cancer 3, 731–738.
Frade, J.M. (2000). Unscheduled re-entry into the cell cycle induced by NGF precedes cell death in nascent retinal neurones. J Cell Sci 113, 1139–1148.
Frade, J.M., and Ovejero-Benito, M.C. (2015). Neuronal cell cycle: The neuron itself and its circumstances. Cell Cycle 14, 712–720.
Giovanni, A., Keramaris, E., Morris, E.J., Hou, S.T., O’Hare, M., Dyson, N., Robertson, G.S., Slack, R.S., and Park, D.S. (2000). E2F1 mediates death of B-amyloid-treated cortical neurons in a manner independent of p53 and dependent on Bax and caspase 3. J. Biol. Chem. 275, 11553–11560.
Lipinski, M.M., Macleod, K.F., Williams, B.O., Mullaney, T.L., Crowley, D., and Jacks, T. (2001). Cell-autonomous and non-cell-autonomous functions of the Rb tumor suppressor in developing central nervous system. EMBO J. 20, 3402–3413.
Liu, D., Nath, N., Chellappan, S., and Greene, L. (2005). Regulation of neuron survival and death by p130 and associated chromatin modifiers. GENES Dev. 18, 719–723.
Liu, N., Lucibello, F.C., Engeland, K., and Müller, R. (1998). A new model of cell cycle-regulated transcription: Repression of the cyclin A promoter by CDF-1 and anti-repression by E2F. Oncogene 16, 2957–2963.
Merrick, K. a, and Fisher, R.P. (2011). Putting one step before the other: distinct activation pathways for Cdk1 and Cdk2 bring order to the mammalian cell cycle. 9, 706–714.
Morillo, S.M., Abanto, E.P., Roman, M.J., and Frade, J.M. (2012). Nerve Growth Factor-Induced Cell Cycle Reentry in Newborn Neurons Is Triggered by p38MAPK-Dependent E2F4 Phosphorylation. Mol. Cell. Biol. 32, 2722–2737.
Park, D.S., Morris, E.J., Padmanabhan, J., Shelanski, M.L., Geller, H.M., and Greene, L. a. (1998). Cyclin-dependent kinases participate in death of neurons evoked by DNA- damaging agents. J. Cell Biol. 143, 457–467.
Smith, D.S., Leone, G., DeGregori, J., Ahmed, M.N., Qumsiyeh, M.B., and Nevins, J.R. (2000). Induction of DNA replication in adult rat neurons by deregulation of the retinoblastoma/E2F G1 cell cycle pathway. Cell Growth Differ. 11, 625–633.
Williams, G.H., and Stoeber, K. (2012). The cell cycle and cancer. 352–364.
Yang, Y., Mufson, E.J., and Herrup, K. (2003). Neuronal Cell Death Is Preceded by Cell Cycle Events at All Stages of Alzheimer’s Disease. J. Neurosci. 23, 2557–2563.
Yasutis, K.M., and Kozminski, K.G. (2013). Cell cycle checkpoint regulators reach a zillion. Cell Cycle 12, 1501–1509.

Related Research Articles

The cell cycle, or cell-division cycle, is the series of events that take place in a cell that causes it to divide into two daughter cells. These events include the duplication of its DNA and some of its organelles, and subsequently the partitioning of its cytoplasm, chromosomes and other components into two daughter cells in a process called cell division.

Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there are two distinct types of cell division: a vegetative division (mitosis), producing daughter cells genetically identical to the parent cell, and a cell division that produces haploid gametes for sexual reproduction (meiosis), reducing the number of chromosomes from two of each type in the diploid parent cell to one of each type in the daughter cells. Mitosis is a part of the cell cycle, in which, replicated chromosomes are separated into two new nuclei. Cell division gives rise to genetically identical cells in which the total number of chromosomes is maintained. In general, mitosis is preceded by the S stage of interphase and is followed by telophase and cytokinesis; which divides the cytoplasm, organelles, and cell membrane of one cell into two new cells containing roughly equal shares of these cellular components. The different stages of mitosis all together define the M phase of an animal cell cycle—the division of the mother cell into two genetically identical daughter cells. To ensure proper progression through the cell cycle, DNA damage is detected and repaired at various checkpoints throughout the cycle. These checkpoints can halt progression through the cell cycle by inhibiting certain cyclin-CDK complexes. Meiosis undergoes two divisions resulting in four haploid daughter cells. Homologous chromosomes are separated in the first division of meiosis, such that each daughter cell has one copy of each chromosome. These chromosomes have already been replicated and have two sister chromatids which are then separated during the second division of meiosis. Both of these cell division cycles are used in the process of sexual reproduction at some point in their life cycle. Both are believed to be present in the last eukaryotic common ancestor.

Cyclins are proteins that control the progression of a cell through the cell cycle by activating cyclin-dependent kinases (CDK).

Cyclin-dependent kinases (CDKs) are a predominant group of serine/threonine protein kinases involved in the regulation of the cell cycle and its progression, ensuring the integrity and functionality of cellular machinery. These regulatory enzymes play a crucial role in the regulation of eukaryotic cell cycle and transcription, as well as DNA repair, metabolism, and epigenetic regulation, in response to several extracellular and intracellular signals. They are present in all known eukaryotes, and their regulatory function in the cell cycle has been evolutionarily conserved. The catalytic activities of CDKs are regulated by interactions with CDK inhibitors (CKIs) and regulatory subunits known as cyclins. Cyclins have no enzymatic activity themselves, but they become active once they bind to CDKs. Without cyclin, CDK is less active than in the cyclin-CDK heterodimer complex. CDKs phosphorylate proteins on serine (S) or threonine (T) residues. The specificity of CDKs for their substrates is defined by the S/T-P-X-K/R sequence, where S/T is the phosphorylation site, P is proline, X is any amino acid, and the sequence ends with lysine (K) or arginine (R). This motif ensures CDKs accurately target and modify proteins, crucial for regulating cell cycle and other functions. Deregulation of the CDK activity is linked to various pathologies, including cancer, neurodegenerative diseases, and stroke.

A cyclin-dependent kinase complex is a protein complex formed by the association of an inactive catalytic subunit of a protein kinase, cyclin-dependent kinase (CDK), with a regulatory subunit, cyclin. Once cyclin-dependent kinases bind to cyclin, the formed complex is in an activated state. Substrate specificity of the activated complex is mainly established by the associated cyclin within the complex. Activity of CDKCs is controlled by phosphorylation of target proteins, as well as binding of inhibitory proteins.

S phase (Synthesis phase) is the phase of the cell cycle in which DNA is replicated, occurring between G₁ phase and G₂ phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S-phase are tightly regulated and widely conserved.

G₂ phase, Gap 2 phase, or Growth 2 phase, is the third subphase of interphase in the cell cycle directly preceding mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated. G₂ phase ends with the onset of prophase, the first phase of mitosis in which the cell’s chromatin condenses into chromosomes.

The restriction point (R), also known as the Start or G₁/S checkpoint, is a cell cycle checkpoint in the G₁ phase of the animal cell cycle at which the cell becomes "committed" to the cell cycle, and after which extracellular signals are no longer required to stimulate proliferation. The defining biochemical feature of the restriction point is the activation of G₁/S- and S-phase cyclin-CDK complexes, which in turn phosphorylate proteins that initiate DNA replication, centrosome duplication, and other early cell cycle events. It is one of three main cell cycle checkpoints, the other two being the G2-M DNA damage checkpoint and the spindle checkpoint.

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase, in which the cell grows, and the S phase, during which DNA is replicated. It is governed by cell cycle checkpoints to ensure cell cycle integrity and the subsequent S phase can pause in response to improperly or partially replicated DNA. During this transition the cell makes decisions to become quiescent, differentiate, make DNA repairs, or proliferate based on environmental cues and molecular signaling inputs. The G1/S transition occurs late in G1 and the absence or improper application of this highly regulated checkpoint can lead to cellular transformation and disease states such as cancer.

Cyclin A is a member of the cyclin family, a group of proteins that function in regulating progression through the cell cycle. The stages that a cell passes through that culminate in its division and replication are collectively known as the cell cycle Since the successful division and replication of a cell is essential for its survival, the cell cycle is tightly regulated by several components to ensure the efficient and error-free progression through the cell cycle. One such regulatory component is cyclin A which plays a role in the regulation of two different cell cycle stages.

<span class="mw-page-title-main">Cyclin D</span> Member of the cyclin protein family

Cyclin D is a member of the cyclin protein family that is involved in regulating cell cycle progression. The synthesis of cyclin D is initiated during G1 and drives the G1/S phase transition. Cyclin D protein is anywhere from 155 to 477 amino acids in length.

Cell division protein kinase 6 (CDK6) is an enzyme encoded by the CDK6 gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of the cyclin-dependent kinase, (CDK) family, which includes CDK4. CDK family members are highly similar to the gene products of Saccharomyces cerevisiae cdc28, and Schizosaccharomyces pombe cdc2, and are known to be important regulators of cell cycle progression in the point of regulation named R or restriction point.

CDK7 is a cyclin-dependent kinase shown to be not easily classified. CDK7 is both a CDK-activating kinase (CAK) and a component of the general transcription factor TFIIH.

A cyclin-dependent kinase inhibitor protein(also known as CKIs, CDIs, or CDKIs) is a protein which inhibits the enzyme cyclin-dependent kinase (CDK) and Cyclin activity by stopping the cell cycle if there are unfavorable conditions, therefore, acting as tumor suppressors. Cell cycle progression is stopped by Cyclin-dependent kinase inhibitor protein at the G1 phase. CKIs are vital proteins within the control system that point out whether the process of DNA synthesis, mitosis, and cytokines control one another. If a malfunction prevents the successful completion of DNA synthesis during the G1 phase, a signal is sent to delay or stop the progression to the S phase. Cyclin-dependent kinase inhibitor proteins are essential in the regulation of the cell cycle. If cell mutations surpass the cell cycle checkpoints during cell cycle regulation, it can result in various types of cancer.

Wee1 is a nuclear kinase belonging to the Ser/Thr family of protein kinases in the fission yeast Schizosaccharomyces pombe. Wee1 has a molecular mass of 96 kDa and is a key regulator of cell cycle progression. It influences cell size by inhibiting the entry into mitosis, through inhibiting Cdk1. Wee1 has homologues in many other organisms, including mammals.

A series of biochemical switches control transitions between and within the various phases of the cell cycle. The cell cycle is a series of complex, ordered, sequential events that control how a single cell divides into two cells, and involves several different phases. The phases include the G1 and G2 phases, DNA replication or S phase, and the actual process of cell division, mitosis or M phase. During the M phase, the chromosomes separate and cytokinesis occurs.

The G₂-M DNA damage checkpoint is an important cell cycle checkpoint in eukaryotic organisms that ensures that cells don't initiate mitosis until damaged or incompletely replicated DNA is sufficiently repaired. Cells with a defective G₂-M checkpoint will undergo apoptosis or death after cell division if they enter the M phase before repairing their DNA. The defining biochemical feature of this checkpoint is the activation of M-phase cyclin-CDK complexes, which phosphorylate proteins that promote spindle assembly and bring the cell to metaphase.

The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in several major cancers. One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. When the cell is ready to divide, pRb is phosphorylated, inactivating it, and the cell cycle is allowed to progress. It is also a recruiter of several chromatin remodeling enzymes such as methylases and acetylases.

The Cyclin E/Cdk2 complex is a structure composed of two proteins, cyclin E and cyclin-dependent kinase 2 (Cdk2). Similar to other cyclin/Cdk complexes, the cyclin E/Cdk2 dimer plays a crucial role in regulating the cell cycle, with this specific complex peaking in activity during the G1/S transition. Once the two cyclin and Cdk subunits are joined together, the complex becomes activated and proceeds to phosphorylate and bind to downstream proteins to ultimately promote cell cycle progression. Although cyclin E can bind to other Cdk proteins, its primary binding partner is Cdk2, and the majority of cyclin E activity occurs when it exists as the cyclin E/Cdk2 complex.

References

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