The Neuronal Cell Cycle and Its Distinctive Features
The neuronal cell cycle is a critical process for neuron function and survival, involving phases like G1, S, and G2, but avoiding cell division in mature neurons. This cycle is tightly regulated by cyclins and Cdks, with disruptions leading to diseases such as Alzheimer's. Neurons may re-enter the cycle in response to injury, often resulting in cell death. However, some neurons can replicate DNA without apoptosis, contributing to neuronal diversity and development.
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The Neuronal Cell Cycle and Its Distinctive Features
The neuronal cell cycle refers to the series of events that neurons undergo from their birth to their eventual degeneration. Unlike other cell types, mature neurons in the adult brain do not typically divide. The cell cycle includes the G1 phase, where the cell grows and prepares for DNA synthesis; the S phase, where DNA replication occurs; and the G2 phase, where the cell prepares for mitosis. However, neurons usually enter a resting state called G0 and do not proceed with cell division. In some cases, such as in response to injury or disease, neurons may attempt to re-enter the cell cycle, a process known as "abortive cell cycle re-entry," which can lead to cell death due to incomplete DNA replication or other disruptions.Neuronal Cell Cycle Control Mechanisms
The neuronal cell cycle is regulated by a balance between cyclins and cyclin-dependent kinases (Cdks). Cyclins activate Cdks, which then phosphorylate specific target proteins to advance the cell cycle. During the G1 phase, cyclin D partners with Cdk4/6 to phosphorylate the retinoblastoma (Rb) protein, releasing the transcription factor E2F1, which is crucial for initiating DNA synthesis. The transition from G1 to S phase is further controlled by cyclin E and Cdk2. Cyclin A collaborates with Cdk2 and later Cdk1 to support DNA replication and prepare for mitosis. The G2/M transition is managed by the Cdk1/cyclin B complex. Cell cycle inhibitors from the Ink4 and Cip/Kip families prevent premature activation of cyclin/Cdk complexes, ensuring that cells only progress when conditions are appropriate. These checkpoints are vital for preserving genomic stability and preventing unregulated cell proliferation.Consequences of Neuronal Cell Cycle Re-entry
Post-mitotic neurons typically reside in the G0 phase and do not divide. However, they retain core cell cycle machinery, which is implicated in processes such as neuronal migration and synaptic plasticity. Pathological triggers can induce an aberrant re-entry into the cell cycle, marked by an increase in cyclin D-Cdk4/6 activity and a decrease in E2F levels, often leading to neuronal death. In certain neuronal types, such as cerebellar granule cells, E2F1 can initiate apoptosis through pathways involving Bax and caspase-3 or the Cdk1/FOXO1/Bad pathway. Disruption of the p130/E2F4 complex, which helps maintain the post-mitotic state, can also trigger apoptosis by upregulating pro-apoptotic genes.Cell Cycle Re-entry in Select Neuronal Types
Although DNA replication in neurons typically results in cell death, certain types, such as sensory and sympathetic neurons, can replicate their DNA without undergoing apoptosis. Tetraploid neurons, which contain double the normal amount of DNA, have been identified in various neuronal populations, including in the human cortex. These neurons can persist in a tetraploid state, sometimes due to a deficiency in Rb protein. In the developing chick retina, DNA replication can contribute to neuronal diversity. The mechanisms allowing these neurons to evade the G1/S checkpoint and avoid apoptosis are not fully understood, but factors such as p75NTR have been implicated in facilitating cell cycle re-entry through Cdk4/6-independent pathways.Cell Cycle Re-entry and Neurodegenerative Disorders
In neurodegenerative diseases like Alzheimer's, neurons that aberrantly re-enter the cell cycle are more susceptible to apoptosis, which exacerbates the disease. These neurons show evidence of DNA replication and the presence of cell cycle proteins, yet they seldom complete mitosis, often remaining in a tetraploid state. The G2/M checkpoint seems to be critical for the survival of these neurons, as bypassing it can lead to cell death. The precise mechanisms by which neurons undergo apoptosis following the G2/M transition are not fully elucidated, but it is known that Cdk1 can activate pro-apoptotic factors such as Bad.Interkinetic Nuclear Migration and Neural Development
Interkinetic nuclear migration (INM) is a phenomenon observed in the developing neural tissue, where the nuclei of progenitor cells move in coordination with the cell cycle. Nuclei are positioned near the basal side during the S phase and migrate to the apical ventricular side for mitosis. This movement is believed to efficiently utilize space within the developing neuroepithelium and is essential for proper mitotic spindle assembly. While INM is not a requirement for the cell cycle itself, it is modulated by cell cycle regulators, highlighting the interplay between nuclear positioning and cell cycle progression during neural development.Want to create maps from your material?
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Neuronal cell cycle phases
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Mature neuron division in adult brain
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Abortive cell cycle re-entry
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4
In the ______ phase, cyclin D joins forces with ______ to phosphorylate the Rb protein, which frees E2F1, a key factor for starting DNA synthesis.
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The progression from G1 to ______ phase is further regulated by cyclin ______ and ______.
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Cell cycle inhibitors from the ______ and ______ families help prevent early activation of cyclin/Cdk complexes, crucial for genomic stability.
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7
Post-mitotic neuron phase
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Cyclin D-Cdk4/6 role in neurons
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p130/E2F4 complex function
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10
Neurons with double the usual DNA amount, known as ______ neurons, have been found in the human ______.
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Tetraploid neurons may remain due to a lack of ______ protein.
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Rb
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In the ______ retina, DNA replication contributes to the variety of neurons.
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13
The exact processes that allow neurons to bypass the ______ checkpoint and prevent apoptosis are not completely known.
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14
The protein ______ is thought to help neurons re-enter the cell cycle via pathways that do not involve ______.
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Neuronal state post cell cycle re-entry in Alzheimer's
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Role of G2/M checkpoint in neuron survival
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Cdk1's role in neuron apoptosis post G2/M transition
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During the S phase, nuclei are located near the ______ side, and they move to the ______ side for mitosis.
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The purpose of this nuclear movement is to optimize space in the ______ and ensure correct ______ assembly.
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20
Although not essential for the cell cycle, INM is influenced by ______ that control the cycle, showing a connection between nuclear placement and cell cycle ______.
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