Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity
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ABSTRACT:
PROVIDER: PRJNA925188 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23112436_1.fastq.gz | Fastqsanger.gz | |||
| SRR23112436_2.fastq.gz | Fastqsanger.gz | |||
| SRR23112437_1.fastq.gz | Fastqsanger.gz | |||
| SRR23112437_2.fastq.gz | Fastqsanger.gz | |||
| SRR23112438_1.fastq.gz | Fastqsanger.gz |
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Project description:The functional output of the hippocampus, a brain region subserving memory processes, depends on highly orchestrated cellular and molecular processes that regulate synaptic plasticity throughout life. The structural requirements of such plasticity and molecular processes involved in this regulation are poorly understood. Specific molecules, including tissue inhibitor of metalloproteinases-2 (TIMP2) have been implicated in serving a pro-plasticity role in the hippocampus, a role that decreases with brain aging. Here, we report that TIMP2 is highly expressed by neurons within the hippocampus and its loss drives changes in cellular programs related to adult neurogenesis and dendritic spine turnover with corresponding impairments in hippocampus-dependent memory. We find that TIMP2 regulates accumulation of extracellular matrix (ECM) around synapses in the hippocampus with concomitant hindrance in migration of newborn neurons through a denser ECM network. A conditional TIMP2 KO mouse reveals that neuronal TIMP2 regulates adult neurogenesis, accumulation of ECM, and ultimately hippocampus-dependent memory. Our results define a mechanism whereby hippocampus-dependent function is regulated by TIMP2 and its interactions with the ECM to regulate diverse processes associated with synaptic plasticity.
2023-11-02 | GSE223188 | GEO
Project description:Tissue inhibitors of metalloproteinases (TIMP) are endogenous inhibitors of matrix metalloproteinases (MMP). While TIMP2 and TIMP3 inhibit MMPs, TIMP3 also inhibits activation of pro-MMP2 whereas TIMP2 promotes it. Here we assessed the differential role of TIMP2 and TIMP3 in renal injury using the unilateral ureteral obstruction model. Gene microarray assay showed that post-obstruction, the lack of TIMP3 had a greater impact on gene expression of intermediate, late injury- and repair-induced transcripts, kidney selective transcripts and solute carriers. Renal injury in TIMP3-/-, but not in TIMP2-/- mice increased expression of collagen type I/III, connective tissue growth factor, transforming growth factor-β and the downstream Smad2/3 pathway. Interestingly, ureteral obstruction markedly increased MMP2 activation in the kidneys of TIMP3-/- mice which was completely blocked in the kidneys of TIMP2-/- mice. These changes are consistent with enhanced renal tubulointerstitial fibrosis in TIMP3-/- and its reduction in TIMP2-/- mice. The activity of tumor necrosis factor-α converting enzyme, caspase-3 and mitogen activated kinases were elevated in the kidneys of TIMP3-/- but not TIMP2-/- mice, suggesting enhanced activation of apoptotic and pathological signaling pathways only in the obstructed kidney of TIMP3-/- mice. Thus, TIMP2 and TIMP3 play differential and contrasting roles in renal injury, TIMP3 protects from damage whereas TIMP2 promotes injury through MMP2 activation. Kidneys from the wild type (WT), TIMP2-/- and TIMP3-/- mice undergoing sham or unilateral ureteral obstruction (UUO) procedures
2013-07-01 | E-GEOD-42303 | biostudies-arrayexpress
Project description:Tissue inhibitors of metalloproteinases (TIMP) are endogenous inhibitors of matrix metalloproteinases (MMP). While TIMP2 and TIMP3 inhibit MMPs, TIMP3 also inhibits activation of pro-MMP2 whereas TIMP2 promotes it. Here we assessed the differential role of TIMP2 and TIMP3 in renal injury using the unilateral ureteral obstruction model. Gene microarray assay showed that post-obstruction, the lack of TIMP3 had a greater impact on gene expression of intermediate, late injury- and repair-induced transcripts, kidney selective transcripts and solute carriers. Renal injury in TIMP3-/-, but not in TIMP2-/- mice increased expression of collagen type I/III, connective tissue growth factor, transforming growth factor-β and the downstream Smad2/3 pathway. Interestingly, ureteral obstruction markedly increased MMP2 activation in the kidneys of TIMP3-/- mice which was completely blocked in the kidneys of TIMP2-/- mice. These changes are consistent with enhanced renal tubulointerstitial fibrosis in TIMP3-/- and its reduction in TIMP2-/- mice. The activity of tumor necrosis factor-α converting enzyme, caspase-3 and mitogen activated kinases were elevated in the kidneys of TIMP3-/- but not TIMP2-/- mice, suggesting enhanced activation of apoptotic and pathological signaling pathways only in the obstructed kidney of TIMP3-/- mice. Thus, TIMP2 and TIMP3 play differential and contrasting roles in renal injury, TIMP3 protects from damage whereas TIMP2 promotes injury through MMP2 activation.
2013-07-01 | GSE42303 | GEO
Project description:Classical methods of investigating protein-protein interactions (PPIs) are generally performed in non-living systems, yet in recent years new technologies utilizing proximity labeling (PL) have given researchers the tools to explore proximal PPIs in living systems. PL has distinct advantages over traditional protein interactome studies, such as the ability to identify weak and transient interactions in vitro and in vivo. Most PL studies are performed on targets within or on the cell membrane. We have adapted the original PL method to investigate PPIs within the extracellular compartment, using both BioID2 and TurboID, that we term extracellular PL (ePL). To demonstrate the utility of this modified technique, we investigate the interactome of the widely expressed matrisome protein Tissue inhibitors of metalloproteinases 2 (TIMP2). Tissue inhibitors of metalloproteinases (TIMPs) are a family of multi-functional proteins that were initially defined by their ability to inhibit the enzymatic activity of metalloproteinases (MPs), the major mediators of extracellular matrix (ECM) breakdown and turnover. TIMP2 exhibits a broad expression profile and is often abundant in both normal and diseased tissues. Understanding the functional transformation of matrisome regulators, like TIMP2, during the evolution of tissue microenvironments associated with disease progression is essential for the development of ECM targeted therapeutics. Using carboxyl- and amino-terminal fusion proteins of TIMP2 with BioID2 and TurboID, we describe the TIMP2 proximal interactome. We also illustrate how the TIMP2 interactome changes in the presence of different stimuli, in different cell types, in unique culture conditions (2D vs 3D), and with different reaction kinetics (BioID2 vs. TurboID); demonstrating the power of this technique versus classical PPI methods. We propose that the screening of matrisome targets in disease models using ePL will reveal new therapeutic targets for further comprehensive studies.
2024-01-09 | GSE252575 | GEO
Project description:Microglial remodeling of the extracellular matrix promotes synapse plasticity
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Project description:Microglial remodeling of the extracellular matrix promotes synapse plasticity [Microglia]
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Project description:Microglial remodeling of the extracellular matrix promotes synapse plasticity [Neuronal nuclei]
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Project description:TIMP2 inhibits metalloproteinase activity and possesses metalloproteinase-independent functions that regulate cell growth, invasion, and gene expression. Although mounting evidence suggests TIMP2 can reduce tumor burden and metastasis the demonstration of these effects using in vivo tumor models are lacking. In this study, we examine the effects of functional mutation of Timp2 and administration of recombinant TIMP2 in models of both orthotopic and heterotopic murine lung cancer using the syngeneic Lewis Lung carcinoma cells (LL/2-luc2). Mice harboring a functional mutation of TIMP2 (mT2) display a marked increase in tumor growth and mortality, enhanced tumor micro-vasculature, and greater infiltration of myeloid-derived cells compared to wt mice, suggesting that reduced TIMP2 function results in enhanced presence of pro-tumorigenic, immunosuppressive myeloid cells. Treatment with recombinant TIMP2 reduced primary tumor growth in both genotypes. Transcriptional profiling of lung tissues from non-tumor-bearing mice reveals minimal changes in mice. However, orthotopic, lung tumor-bearing mice demonstrate significant changes in gene expression that are genotype-dependent. In tumor-bearing wt mice TIMP2-treatment reduced the expression of upstream oncogenic mediators. In comparison, treatment of mT2 mice resulted in an immunomodulatory phenotype, as suggested by enhanced activity of Il4, Il2, and Ifng. A heterotopic model of LL/2 generating metastatic pulmonary tumors demonstrated that daily administration of recombinant TIMP2, while also reducing primary tumor growth, significantly altered transcriptional profiles in the lungs of wt mice, suggesting modification of the metastatic niche. These changes result in the downregulation of cell-stress responses, as evidenced by reduced expression of heat shock proteins. In summary, we describe how TIMP2 exerts novel, anti-tumor effects in a murine model of lung cancer and that rTIMP2 treatment supports a normalizing effect on the tumor microenvironment. These findings support the concept that TIMP2 displays homeostatic functions to reverse cell stress signaling in addition to inhibition of metalloproteinases.
2023-12-22 | GSE251740 | GEO
Project description:The Genomic Architecture of Pregnancy-Associated Plasticity in the Maternal Mouse Hippocampus
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Project description:Astrocyte-secreted IL-33 mediates homeostatic synaptic plasticity in the adult hippocampus
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