ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2005
Tissue inhibitor of metalloproteinase-2 promotes neuronal differentiation by acting as an anti-mitogenic signal.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 120 citations in OpenAlex.
- Engineering a Perfusion Bioreactor System for hiPSC-Derived Progenitor Co-Culture Capturing Microglial Features in CNS Development.Biotechnology and bioengineering · 2026Article
- Systematic Analysis of SH-SY5Y Differentiation Protocols and Neuronal Subtype Abundance.Cellular and molecular neurobiology · 2025Article
- Extracellular Matrix (ECM)-Regulated Molecular Switches: Tissue Inhibitors of Metalloproteinases in Synaptic Formation and Neuropathic Diseases.Cellular and molecular neurobiology · 2025Review
- Music elicits different gene expression responses in the buccal cavity of age-related cognitive disorders patients and healthy controls.Frontiers in aging neuroscience · 2025Article
- Blood-based therapies to combat neurodegenerative diseases.Metabolic brain disease · 2024Review
- RNA-Seq time-course analysis of neural precursor cell transcriptome in response to herpes simplex Virus-1 infection.Journal of neurovirology · 2024Article
- The TIMP protein family: diverse roles in pathophysiology.American journal of physiology. Cell physiology · 2024Review
- TIMP2 ameliorates blood-brain barrier disruption in traumatic brain injury by inhibiting Src-dependent VE-cadherin internalization.The Journal of clinical investigation · 2023Article
- Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity.Molecular psychiatry · 2023Article
- Article
- A single-cell transcriptome atlas of the maturing zebrafish telencephalon.Genome research · 2023Article
- TIMP3 promotes the maintenance of neural stem-progenitor cells in the mouse subventricular zone.Frontiers in neuroscience · 2023Article
- The O-GlcNAc cycling in neurodevelopment and associated diseases.Biochemical Society transactions · 2022Review
- Estrogen Receptor Subtypes Elicit a Distinct Gene Expression Profile of Endothelial-Derived Factors Implicated in Atherosclerotic Plaque Vulnerability.International journal of molecular sciences · 2022Article
- Unravelling the distinct biological functions and potential therapeutic applications of TIMP2 in cancer.Carcinogenesis · 2022Review
- The Biology and Function of Tissue Inhibitor of Metalloproteinase 2 in the Lungs.Pulmonary medicine · 2022Review
- DNA methylation and exposure to violence among African American young adult males.Brain, behavior, & immunity - health · 2021Article
- The 'rejuvenating factor' TIMP-2 is detectable in human blood components for transfusion.Vox sanguinis · 2021Article
- The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases.International journal of molecular sciences · 2020Review
- Differences in the Structure and Protein Expression of Femoral Nerve Branches in Rats.Frontiers in neuroanatomy · 2020Article
6 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Although traditionally recognized for maintaining extracellular matrix integrity during morphogenesis, the function of matrix metallo-proteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), in the mature nervous system is essentially unknown. Here, we report that TIMP-2 induces pheochromocytoma PC12 cell-cycle arrest via regulation of cell-cycle regulatory proteins, resulting in differentiation and neurite outgrowth. TIMP-2 decreases cyclins B and D expression and increases p21Cip expression. Furthermore, TIMP-2 promotes cell differentiation via activation of the cAMP/Rap1/ERK (extracellular signal-regulated kinase) pathway. Expression of dominant-negative Rap1 blocks TIMP-2-mediated neurite outgrowth. Both the cell-cycle arrest and neurite outgrowth induced by TIMP-2 was independent of MMP inhibitory activity. Consistent with the PC12 cell data, primary cultures of TIMP-2 knock-out cerebral cortical neurons exhibit significantly reduced neurite length, which is rescued by TIMP-2. These in vitro results were corroborated in vivo. TIMP-2 deletion causes a delay in neuronal differentiation, as demonstrated by the persistence of nestin-positive progenitors in the neocortical ventricular zone. The interaction of TIMP-2 with alpha3beta1 integrin in the cerebral cortex suggests that TIMP-2 promotes neuronal differentiation and maintains mitotic quiescence in an MMP-independent manner through integrin activation. The identification of molecules responsible for neuronal quiescence has significant implications for the ability of the adult brain to generate new neurons in response to injury and neurological disorders, such as Alzheimer's and Parkinson's diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.