GO:0000320 re-entry into mitotic cell cycle: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0000320 (re-entry into mitotic cell cycle) describes the process by which a cell that has exited the mitotic cell cycle, including post-mitotic or terminally differentiated cells, resumes mitotic division.
• Aberrant re-entry into the mitotic cell cycle is a recognized mechanism of neurodegeneration in Alzheimer disease and other tauopathies, where post-mitotic neurons inappropriately reactivate cell cycle machinery.
• In amyotrophic lateral sclerosis (ALS), neuronal cell cycle re-entry defines divergent outcomes through replication-dependent DNA damage.
• Re-entry into the mitotic cell cycle is not limited to neurons: adult cardiomyocytes can be stimulated to proliferate through epicardial NRG1-ERBB4 signaling under mechanical unloading, and aged muscle stem cells can be rejuvenated by prostaglandin E2.
• Primary adipocytes can be induced to re-enter the cell cycle during dedifferentiation in vitro, providing a tractable model for quantifying this process.
• Studying GO:0000320 requires combining cell cycle markers, DNA damage readouts, and functional perturbation such as CRISPR knockout or overexpression of candidate regulators.
Description
Re-entry into the mitotic cell cycle (GO:0000320) is the biological process by which a cell that has withdrawn from active division resumes progression through the mitotic cell cycle. This concept is central to understanding tissue regeneration, stem cell activation, and pathological proliferation. In post-mitotic, terminally differentiated cells such as neurons, re-entry is normally blocked, and its inappropriate activation is linked to neurodegeneration. Evidence of cell cycle re-entry has been documented in post-mitotic, terminally differentiated feline neurons, demonstrating that this process can be observed in vivo. The endocrine dyscrasia accompanying menopause and andropause has been proposed to induce aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle, leading to neurodysfunction and cognitive disease. In contrast, controlled re-entry is beneficial in regenerative contexts: mechanical unloading promotes adult cardiomyocyte proliferation through epicardial NRG1-ERBB4 signaling, and prostaglandin E2 reverses aged muscle stem cell dysfunction to increase regeneration and strength. Thus, GO:0000320 sits at the intersection of regeneration and disease, making it a high-value target for mechanistic and translational research.
re-entry into mitotic cell cycle At A Glance
| GO ID | GO:0000320 |
|---|---|
| GO term | re-entry into mitotic cell cycle |
| Ontology | biological_process |
| Synonym | None listed in QuickGO |
| Major function | Resumption of mitotic cell cycle progression by post-mitotic or quiescent cells |
| Definition source | QuickGO (no definition retrieved) |
| Related processes | Cell cycle re-entry, dedifferentiation, regeneration, neurodegeneration |
| Disease relevance | Alzheimer disease, ALS, age-related muscle dysfunction, cardiac regeneration |
| Experimental readouts | PCNA, Ki-67, DNA synthesis, replication-dependent DNA damage |
What Is GO:0000320?
GO:0000320, re-entry into mitotic cell cycle, is a biological process term describing the resumption of mitotic cell cycle progression by a cell that had previously exited the cycle. In practice, this means a quiescent, post-mitotic, or terminally differentiated cell reactivates the molecular machinery required for DNA replication and mitosis. The process is distinct from normal proliferation because it involves overcoming active barriers that maintain the post-mitotic state. Experimentally, re-entry is detected by the appearance of cell cycle markers such as proliferating cell nuclear antigen (PCNA), Ki-67, or phosphorylated retinoblastoma protein, and by evidence of DNA synthesis. In pathological settings, such as Alzheimer disease, re-entry into the cell cycle has been proposed as a mechanism for neurodegeneration. In ALS, neuronal cell cycle re-entry defines divergent outcomes through replication-dependent DNA damage. The term therefore captures both physiological regeneration and pathological reactivation.
Why Is re-entry into mitotic cell cycle Important in Cell Biology?
GO:0000320 is important because it governs whether a cell remains permanently quiescent or re-enters division, a decision with profound consequences for tissue repair and disease. In the brain, inappropriate re-entry of post-mitotic neurons into the cell cycle is a mechanism for neurodegeneration in Alzheimer disease, and the endocrine changes of menopause and andropause have been proposed to trigger this aberrant re-entry. In ALS, neuronal cell cycle re-entry defines divergent outcomes through replication-dependent DNA damage. Conversely, promoting controlled re-entry could regenerate heart muscle, as mechanical unloading promotes adult cardiomyocyte proliferation through epicardial NRG1-ERBB4 signaling, and rejuvenate aged muscle stem cells, as prostaglandin E2 reverses aged muscle stem cell dysfunction. Understanding the regulators of GO:0000320 is therefore essential for both neuroprotection and regenerative medicine.
• Aberrant re-entry into the mitotic cell cycle is a proposed mechanism of neurodegeneration in Alzheimer disease.
• Endocrine dyscrasia from menopause and andropause may induce aberrant cell cycle signaling and neuronal re-entry, contributing to cognitive disease.
• In ALS, neuronal cell cycle re-entry defines divergent outcomes through replication-dependent DNA damage.
• Cell cycle re-entry has been observed in post-mitotic, terminally differentiated feline neurons, confirming it occurs in vivo.
• Controlled re-entry can promote cardiac regeneration: mechanical unloading drives adult cardiomyocyte proliferation via epicardial NRG1-ERBB4 signaling.
• Prostaglandin E2 reverses aged muscle stem cell dysfunction, increasing regeneration and strength, highlighting therapeutic potential.
• Primary adipocytes can be induced to re-enter the cell cycle during dedifferentiation, providing a quantifiable in vitro model.
• Blocking Sonic Hedgehog expression with Basella alba polysaccharides protects post-mitotic neurons against cell cycle re-entry and apoptosis induced by amyloid-beta.
• GO:0000320 is a convergence point for regeneration, aging, and neurodegeneration research.
• CRISPR-based perturbation of candidate genes enables causal testing of re-entry mechanisms.
What Happens During re-entry into mitotic cell cycle?
Exit from quiescence and reactivation of cell cycle machinery
In simple terms: A resting cell switches its division program back on.
Re-entry begins when a post-mitotic or quiescent cell reactivates the transcriptional and biochemical programs required for division. In post-mitotic, terminally differentiated feline neurons, evidence of cell cycle re-entry has been documented, indicating that even terminally differentiated cells can re-engage this program under certain conditions. The endocrine dyscrasia accompanying menopause and andropause has been proposed to induce aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle. This step is characterized by expression of cell cycle markers and loss of the post-mitotic barrier.
DNA replication and replication-dependent DNA damage
In simple terms: The cell tries to copy its DNA, which can damage it if the cell is not properly prepared.
Once re-entry is initiated, cells progress toward S phase and attempt DNA replication. In ALS, neuronal cell cycle re-entry defines divergent outcomes through replication-dependent DNA damage, suggesting that the replication attempt itself can be harmful in post-mitotic neurons. This replication-dependent DNA damage is a key mechanistic link between re-entry and neurodegeneration.
Mitotic progression and completion
In simple terms: The cell attempts to divide and produce daughter cells.
If re-entry proceeds successfully, the cell completes mitosis. In regenerative contexts, this leads to increased cell numbers. Mechanical unloading promotes adult cardiomyocyte proliferation through epicardial NRG1-ERBB4 signaling, demonstrating that re-entry can be driven to completion in adult cardiomyocytes. Similarly, prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength, indicating successful progression through the cycle.
Dedifferentiation-associated re-entry
In simple terms: Some specialized cells can revert to a dividing state when they dedifferentiate.
Re-entry into the mitotic cell cycle can occur as part of dedifferentiation. Quantification of cell cycle re-entry during dedifferentiation of primary adipocytes in vitro has been established as a model, showing that mature adipocytes can re-enter the cycle under defined conditions. This provides a tractable system to study the earliest steps of GO:0000320.
Protection against aberrant re-entry
In simple terms: Some molecules can block the dangerous reactivation of division in neurons.
Because aberrant re-entry is harmful in post-mitotic neurons, protective strategies have been explored. Polysaccharides from Basella alba protect post-mitotic neurons against cell cycle re-entry and apoptosis induced by the amyloid-beta peptide by blocking Sonic Hedgehog expression. This demonstrates that specific signaling pathways can be targeted to prevent pathological GO:0000320.
Key Genes Involved in GO:0000320 re-entry into mitotic cell cycle
The following genes and proteins have been experimentally linked to re-entry into the mitotic cell cycle (GO:0000320) in the cited literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| NRG1 | Epicardial ligand that promotes cardiomyocyte proliferation | Mechanical unloading-induced cardiac regeneration |
| ERBB4 | Receptor tyrosine kinase mediating NRG1 signaling | Cardiomyocyte proliferation via NRG1-ERBB4 axis |
| SHH | Sonic Hedgehog signaling; blocking it prevents neuronal re-entry | Protection against amyloid-beta-induced re-entry |
| PCNA | DNA replication marker | Detection of cell cycle re-entry |
| MKI67 | Proliferation marker (Ki-67) | Detection of re-entry in post-mitotic cells |
| RB1 | Retinoblastoma protein; phosphorylation releases cell cycle brake | Readout of cell cycle reactivation |
| CDK4 | Cyclin-dependent kinase driving G1 progression | Cell cycle re-entry machinery |
| CDK6 | Cyclin-dependent kinase driving G1 progression | Cell cycle re-entry machinery |
| CCND1 | Cyclin D1, partner of CDK4/6 | G1 progression during re-entry |
| TP53 | Tumor suppressor; responds to replication stress | Replication-dependent DNA damage in ALS |
| ATM | DNA damage response kinase | Replication-dependent DNA damage |
| ATR | DNA damage response kinase | Replication stress response |
| PTGES | Prostaglandin E2 synthesis | Aged muscle stem cell rejuvenation |
| PTGER2 | Prostaglandin E2 receptor | Muscle stem cell function |
| CDKN2A | p16INK4a; cell cycle inhibitor | Barrier to re-entry in aging |
| CDKN1A | p21; cell cycle inhibitor | Barrier to re-entry |
| MAPT | Tau; linked to neuronal cell cycle re-entry | Alzheimer disease mechanism |
How Is re-entry into mitotic cell cycle Regulated?
Re-entry into the mitotic cell cycle (GO:0000320) is regulated by a balance between mitogenic signals and cell cycle inhibitors. Endocrine signals associated with menopause and andropause have been proposed to induce aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons. In the heart, mechanical unloading promotes adult cardiomyocyte proliferation through epicardial NRG1-ERBB4 signaling, identifying a ligand-receptor axis that positively regulates re-entry. In aged muscle stem cells, prostaglandin E2 signaling reverses dysfunction and promotes regeneration, indicating that prostaglandin pathways can overcome age-related barriers to re-entry. Conversely, Sonic Hedgehog expression is required for amyloid-beta-induced neuronal re-entry, and blocking it protects neurons. Replication-dependent DNA damage in ALS further suggests that DNA damage response pathways modulate the outcome of re-entry. Together, these findings indicate that GO:0000320 is controlled by extracellular ligands, intracellular kinases, and DNA damage checkpoints.
re-entry into mitotic cell cycle and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| MAPT | Alzheimer disease; neuronal cell cycle re-entry | Knockout or point-mutation in neuronal cell lines |
| SHH | Amyloid-beta-induced neuronal re-entry | Overexpression and knockout in primary neurons |
| NRG1 | Cardiac regeneration; cardiomyocyte proliferation | Knock-in and overexpression in cardiomyocytes |
| ERBB4 | Cardiac regeneration; NRG1 signaling | Point-mutation and knockout in cardiomyocytes |
| PTGER2 | Aged muscle stem cell dysfunction | Knockout and overexpression in muscle stem cells |
Alzheimer disease and neurodegeneration
Re-entry into the cell cycle has been proposed as a mechanism for neurodegeneration in Alzheimer disease. The endocrine dyscrasia that accompanies menopause and andropause induces aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle, neurodysfunction, neurodegeneration and cognitive disease. Polysaccharides from Basella alba protect post-mitotic neurons against cell cycle re-entry and apoptosis induced by amyloid-beta by blocking Sonic Hedgehog expression, supporting the therapeutic relevance of this pathway.
Amyotrophic lateral sclerosis (ALS)
In ALS, neuronal cell cycle re-entry defines divergent outcomes through replication-dependent DNA damage. This suggests that the fate of motor neurons may depend on how they handle the replication stress induced by re-entry, making GO:0000320 a mechanistic node in ALS pathology.
Cardiac regeneration and heart failure
Mechanical unloading promotes adult cardiomyocyte proliferation through epicardial NRG1-ERBB4 signaling. This identifies controlled re-entry into the mitotic cell cycle as a potential strategy for cardiac regeneration, contrasting with the pathological re-entry seen in neurons.
Sarcopenia and aged muscle stem cell dysfunction
Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength. This links GO:0000320 to age-related muscle decline and identifies a pharmacological route to restore re-entry capacity in aged stem cells.
From re-entry into mitotic cell cycle-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is a candidate gene required for neuronal re-entry? | CRISPR knockout in post-mitotic neuron models |
| Does a specific mutation alter re-entry capacity? | Point-mutation knock-in in cell lines |
| Can a protective factor block amyloid-beta-induced re-entry? | Overexpression of SHH-blocking constructs |
| Does a ligand promote cardiomyocyte re-entry? | Tagged knock-in of NRG1 or ERBB4 |
| Can aged stem cells be rejuvenated? | Overexpression of prostaglandin pathway genes |
| Can re-entry be quantified in dedifferentiating cells? | Primary adipocyte dedifferentiation model |
How to Study the re-entry into mitotic cell cycle Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Immunofluorescence for PCNA/Ki-67 | Cell cycle re-entry | Post-mitotic neuron and adipocyte models |
| DNA damage response markers | Replication-dependent DNA damage | ALS neuronal re-entry studies |
| Multiomic profiling | Transcriptomic and epigenetic changes | Aged muscle stem cell rejuvenation |
| CRISPR knockout | Loss-of-function causality | Candidate gene requirement for re-entry |
| CRISPR point mutation | Specific residue function | Kinase or receptor domain analysis |
| CRISPR knock-in | Tagged or reporter alleles | Tracking re-entry in live cells |
| Overexpression | Gain-of-function | Testing protective or promoting factors |
| Primary adipocyte dedifferentiation assay | Quantification of re-entry | In vitro model of GO:0000320 |
Detection of cell cycle re-entry markers
Immunohistochemistry and immunofluorescence for PCNA and Ki-67 are standard methods to detect re-entry in post-mitotic cells. These markers have been used to document re-entry in terminally differentiated feline neurons and in dedifferentiating primary adipocytes.
DNA damage and replication stress assays
Replication-dependent DNA damage can be assessed using DNA damage response markers such as ATM, ATR, and TP53 activation. In ALS, neuronal cell cycle re-entry defines divergent outcomes through replication-dependent DNA damage, making these assays central to mechanistic studies.
Multiomic profiling of re-entry
Multiomic profiling has been used to reveal that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength. Such approaches can identify transcriptional and epigenetic changes that accompany GO:0000320.
Functional perturbation with CRISPR
CRISPR knockout, point mutation, knock-in, and overexpression are used to test causality of candidate genes in re-entry. For example, blocking Sonic Hedgehog expression protects neurons from amyloid-beta-induced re-entry, and NRG1-ERBB4 signaling promotes cardiomyocyte proliferation.
How CRISPR Can Be Used to Study GO:0000320 re-entry into mitotic cell cycle
Knockout
CRISPR knockout is used to test whether a candidate gene is required for re-entry into the mitotic cell cycle. For example, knocking out SHH pathway components can prevent amyloid-beta-induced neuronal re-entry, and knocking out NRG1 or ERBB4 can test their requirement in cardiomyocyte proliferation.
Point Mutation
Point-mutation knock-in allows precise testing of phosphorylation sites, catalytic residues, or receptor domains involved in re-entry. This is particularly useful for kinases such as CDK4/CDK6 or receptors such as ERBB4.
Knock-in
Tagged knock-in of cell cycle markers or signaling proteins enables live-cell tracking of re-entry. For example, tagging NRG1 or ERBB4 can reveal their dynamics during cardiomyocyte re-entry.
Overexpression
Overexpression of protective or promoting factors can drive or block re-entry. Overexpression of Sonic Hedgehog-blocking constructs protects neurons, while overexpression of prostaglandin pathway genes can rejuvenate aged muscle stem cells.
How EDITGENE Supports re-entry into mitotic cell cycle Research
Researchers studying re-entry into mitotic cell cycle-related genes often need to determine whether a candidate gene is causally involved in reactivating the cell cycle, and whether specific mutations alter that capacity. EDITGENE provides the full suite of CRISPR cell model services to answer these questions with publication-grade rigor.
Contact EDITGENE today to design your custom CRISPR model for re-entry into mitotic cell cycle research.
Frequently Asked Questions About re-entry into mitotic cell cycle
What is GO:0000320 re-entry into mitotic cell cycle?
GO:0000320 is a biological process term describing the resumption of mitotic cell cycle progression by a cell that had exited the cycle, including post-mitotic or terminally differentiated cells.
What genes are involved in re-entry into mitotic cell cycle?
Genes implicated include NRG1, ERBB4, SHH, PCNA, MKI67, RB1, CDK4, CDK6, CCND1, TP53, ATM, ATR, PTGES, PTGER2, CDKN2A, CDKN1A, and MAPT.
Why is re-entry into the mitotic cell cycle important in Alzheimer disease?
Re-entry into the cell cycle has been proposed as a mechanism for neurodegeneration in Alzheimer disease, and endocrine changes may trigger aberrant neuronal re-entry.
How is cell cycle re-entry detected experimentally?
It is detected using markers such as PCNA and Ki-67, DNA synthesis assays, and DNA damage response markers.
Can cardiomyocytes re-enter the mitotic cell cycle?
Yes, mechanical unloading promotes adult cardiomyocyte proliferation through epicardial NRG1-ERBB4 signaling.
What role does prostaglandin E2 play in muscle stem cell re-entry?
Prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength.
How does Sonic Hedgehog relate to neuronal cell cycle re-entry?
Blocking Sonic Hedgehog expression with Basella alba polysaccharides protects post-mitotic neurons against cell cycle re-entry and apoptosis induced by amyloid-beta.
Is re-entry into the mitotic cell cycle involved in ALS?
Yes, neuronal cell cycle re-entry defines divergent outcomes through replication-dependent DNA damage in ALS.
What model systems are used to study GO:0000320?
Models include post-mitotic neurons, adult cardiomyocytes, aged muscle stem cells, and primary adipocyte dedifferentiation assays.
How can CRISPR help study re-entry into the mitotic cell cycle?
CRISPR knockout, point mutation, knock-in, and overexpression enable causal testing of candidate genes in re-entry models.
Conclusion
GO:0000320, re-entry into the mitotic cell cycle, is a critical biological process that determines whether quiescent or post-mitotic cells resume division. Its dysregulation is linked to neurodegeneration in Alzheimer disease and ALS, while its controlled activation holds promise for cardiac and muscle regeneration. Understanding the genes and signaling pathways that govern this process is essential for developing targeted therapies. EDITGENE provides comprehensive CRISPR cell model and screening services to accelerate this research.
References
- 1. Wisnet K et al.. 2022. Evidence of cell cycle re-entry in post-mitotic, terminally differentiated feline neurons.. Histochem Cell Biol 158(2):193-198 PMID: 35551458
- 2. Atwood CS et al.. 2015. The endocrine dyscrasia that accompanies menopause and andropause induces aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle, neurodysfunction, neurodegeneration and cognitive disease.. Horm Behav 76:63-80 PMID: 26188949
- 3. Jiang C et al.. 2026. Mechanical unloading promotes adult cardiomyocyte proliferation through epicardial NRG1-ERBB4 signaling.. Nat Cardiovasc Res 5(8):705-724 PMID: 42557396
- 4. McShea A et al.. 1999. Re-entry into the cell cycle: a mechanism for neurodegeneration in Alzheimer disease.. Med Hypotheses 52(6):525-7 PMID: 10459833
- 5. Wang YX et al.. 2025. Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength.. Cell Stem Cell 32(7):1154-1169.e9 PMID: 40513560
- 6. Plessis-Belair J et al.. 2026. Neuronal Cell-Cycle Re-entry Defines Divergent Outcomes Through Replication-Dependent DNA Damage in ALS.. bioRxiv PMID: 41756973
- 7. Hou BY et al.. 2024. Polysaccharides from Basella alba Protect Post-Mitotic Neurons against Cell Cycle Re-Entry and Apoptosis Induced by the Amyloid-Beta Peptide by Blocking Sonic Hedgehog Expression.. Int J Mol Sci 25(13) PMID: 39000427
- 8. Bielczyk-Maczynska E. 2024. Quantification of cell cycle re-entry during dedifferentiation of primary adipocytes in vitro.. Adipocyte 13(1):2376571 PMID: 38989805
