C1Q Mouse
Description
Key Molecular Features
Canonical Complement Activation
C1q initiates the classical pathway by binding antibody-antigen complexes, triggering sequential activation of C1r and C1s proteases. This leads to:
Non-Canonical Functions
Global vs. Macrophage-Specific C1q Deficiency
| Model Type | Phenotype | Clinical Relevance |
|---|---|---|
| Global C1qa−/− | Autoimmunity, bacterial infections, reduced tumor growth, and prolonged bleeding | SLE, neurodegeneration, cancer |
| Macrophage-Specific (CKO) | Reduced tumor-associated macrophage infiltration and angiogenesis | Cancer immunotherapy |
Key Experimental Findings
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Hemostasis: C1q-deficient mice exhibit 4.2-fold greater blood loss than wild-type (WT) mice during tail bleeding assays. Reconstitution with human C1q partially restores hemostasis .
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Tumor Microenvironment: C1q-deficient mice show reduced pleural tumor volume and extended survival in metastatic lung adenocarcinoma models .
Therapeutic and Diagnostic Potential
Product Specs
C1q, the initial component in the classical complement pathway, forms the C1 complex with C1r and C1s, its enzymatically active counterparts. Upon binding to immune complexes via immunoglobulins, C1 activates, triggering the C1r and C1s proteases and initiating the complement cascade. This glycoprotein, a member of the collectin family, weighs approximately 410-462 kDa and comprises six globular heads linked to collagen-like triple-helix tails. The globular heads exhibit specific binding to the CH2 domain of IgG or the CH3 domain of IgM. Activation requires C1q to bind at least two immunoglobulin heavy chains, inducing a conformational change that activates C1r and C1s. Consequently, activation is contingent upon C1q binding to multivalent antigen-bound immunoglobulin immune complexes. A key physiological role of C1q is clearing immune complexes and apoptotic bodies. Disruption of this process can trigger autoimmunity. Genetic deficiencies in C1q or other classical pathway components increase susceptibility to Systemic Lupus Erythematosus (SLE). C1q demonstrates specific binding to apoptotic bodies from human keratinocytes, vascular endothelial cells, and lymphocytes. Complement components C1q and C3, when bound, mediate apoptotic body clearance. Thus, C1q contributes to autoantigen removal, mitigating immune system stimulation. However, prolonged exposure to the neoepitope on immune complex-bound or apoptotic body-bound C1q can elicit an autoimmune response against C1q itself, disrupting complement function. C1q deficiency can also hinder the negative selection of autoreactive B cells. C1q, along with other recognition proteins, binds to conserved lupus antigens like dsDNA and nuclear proteins, activating the complement system. Anti-C1q autoantibodies are found in various autoimmune and infectious diseases, including glomerulonephritis (GN) and SLE, and hold clinical significance due to their negative predictive value.
Mouse Complement C1Q, with a molecular weight of 439.5 kDa, is produced in Mouse plasma.
The product is a sterile-filtered solution.
The C1Q solution is formulated in 10mM HEPES buffer with 300mM NaCl, at a pH of 7.2.
Mouse C1Q remains stable at 4°C for 2-4 weeks, provided the entire vial is used within this period. For extended storage, freezing below -20°C is recommended. Adding a carrier protein (0.1% HSA or BSA) is advisable for long-term storage. Repeated freezing and thawing cycles should be avoided.
The purity of the product is greater than 92.0% as determined by SDS-PAGE analysis.
Component C1q, Complement C1q, Complement Component C1q, C1q.
Mouse Plasma.
Q&A
What is C1q and what is its fundamental role in mouse models?
C1q is the initiating component of the classical complement pathway, encoded by the gene C1QA (complement C1q A chain). In mice, C1q is a 245-amino acid protein with an approximate mass of 26,017 daltons that is primarily secreted and contains glycosylation sites . It functions as a pattern recognition molecule that binds to immune complexes, apoptotic cells, and pathogen surfaces to activate the complement cascade.
In mouse models, C1q plays diverse roles beyond immunity, including:
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Mediating synaptic pruning by microglia in the central nervous system
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Regulating protein synthesis in neurons
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Influencing stress-induced behavioral responses
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Modulating macrophage polarization and function in disease models
C1q knockout mice have been valuable for understanding these various functions, as they exhibit altered immune responses, behavioral changes, and disease susceptibility profiles .
What are the established methods for studying C1q in mouse models?
Researchers employ several complementary approaches to investigate C1q function:
When selecting antibodies for C1q detection, researchers must carefully consider specificity, as different antibodies target distinct epitopes and may have varying cross-reactivity profiles across species .
How is C1q expression regulated in different mouse tissues?
C1q expression shows tissue-specific and context-dependent regulation:
Age-dependent regulation: C1q levels increase in the aging mouse brain, particularly in microglia, suggesting age-related transcriptional changes .
Stress-responsive modulation: Studies have found significant reductions in C1q mRNA levels in the prefrontal cortex of wild-type helpless mice compared to naïve mice, indicating stress-responsive regulation .
Macrophage polarization dynamics: C1q expression is gradually upregulated during M2 macrophage polarization, establishing a potential feedback loop where initial C1q expression reinforces the M2 program .
Inflammatory context: In neuroinflammatory conditions, C1q expression can be altered in response to local cytokine milieu and microglial activation states.
These complex regulatory patterns highlight the importance of considering developmental stage, age, and physiological context when interpreting C1q expression data in experimental models.
How does microglial C1q interact with neurons in aging mouse brains?
Recent research has uncovered a novel function of C1q in regulating neuronal protein synthesis. In the June 2024 Cell publication, Scott-Hewitt and colleagues demonstrated that microglial C1q can infiltrate neuronal ribosomes in year-old mice . This interaction has several important characteristics:
Ribosomal infiltration: Immunostaining revealed C1q (red) within neuronal structures, specifically colocalizing with ribosomal components in aging mouse brains .
RNA dependency: This association is RNA-dependent, as RNase treatment abolished the C1q signal, indicating RNA serves as a critical mediator for C1q's interaction with the translational machinery .
Phase separation mechanism: In vitro experiments showed C1q and RNA form liquid droplets through liquid-liquid phase separation (LLPS), suggesting a mechanism by which C1q sequesters transcripts in the brain .
Functional impact: The consequence of this interaction is significant - year-old mice lacking C1q demonstrated increased protein production rates compared to wild-type mice, indicating C1q acts as a brake on neuronal translation .
Age-dependent effects: The researchers proposed that "C1q may regulate translation in neurons of younger mice, but with age, these interactions turn more gel-like, clamping down on translation too much" . This suggests a transition from adaptive regulation to potentially pathological inhibition with advancing age.
This discovery expands our understanding of how microglia-derived proteins can directly modulate fundamental neuronal processes and may have implications for age-related cognitive decline and neurodegenerative diseases .
What is C1q's role in stress-induced behavioral changes in mouse models?
C1q plays a complex and sometimes counterintuitive role in stress-induced behavioral changes:
Learned helplessness model findings: Using the learned helplessness (LH) model of depression, researchers found that C1q deletion exacerbated inescapable electric foot shock-induced learned helplessness behavior in mice . This suggests C1q may actually be protective against certain stress-induced behavioral changes.
Behavioral specificity: Importantly, C1q knockout did not affect all behaviors. The study observed no significant changes in social behavior, despair behavior, spatial memory, or aggressive behavior between wild-type and C1q knockout mice . This indicates C1q's role is specific to certain stress-response pathways.
Prefrontal cortex regulation: The researchers found significant reductions in C1q mRNA levels in the prefrontal cortex (PFC) of wild-type helpless mice compared to naïve mice . This region-specific downregulation suggests C1q expression changes may be part of the brain's adaptive response to stress.
Inflammatory consequences: Despite its protective behavioral role, C1q deletion led to increased levels of pro-inflammatory cytokines in the PFC of C1q KO mice . This finding reveals a complex relationship between complement activation, inflammation, and behavioral outcomes.
| Group | Behavioral Response to Stress | C1q mRNA in PFC | Inflammatory Markers |
|---|---|---|---|
| Wild-type naive | Normal | Baseline | Normal |
| Wild-type helpless | Moderate helplessness | Reduced | Moderately elevated |
| C1q KO | Enhanced helplessness | Absent | Significantly elevated |
These findings suggest that the classical complement pathway modulates learned helplessness behavior and is accompanied by neuroinflammatory changes under stressful conditions .
How does C1q deficiency affect macrophage function in mouse disease models?
C1q deficiency has profound effects on macrophage function and disease progression in mouse models:
Impact on macrophage polarization: Single-cell RNA sequencing analysis of C1qa-/- mouse malignant pleural effusion (MPE) models revealed that C1q deficiency significantly decreased the proportion of M2 macrophages . This suggests C1q promotes alternative activation toward an immunosuppressive phenotype.
In vitro polarization dynamics: C1q expression was gradually upregulated during M2 polarization, and this process was C1q-dependent . This indicates a potential feed-forward mechanism where initial C1q expression reinforces the M2 polarization program.
Effects on immune cell interactions: Deficiency of C1q in macrophages rescued the exhausted status of CD8+ T cells and enhanced the immune activity of both CD8+ T cells and NK cells in MPE and pleural tumors .
Signaling pathway modulation: Cell-to-cell interaction analysis demonstrated that C1q deficiency attenuated the immunoinhibitory effects of macrophages on NK cells by downregulating the CCR2-CCL2 signaling axis .
Metabolic consequences: Metabolomic analysis revealed significantly elevated hippuric acid levels in C1q-deficient mouse MPE . Treatment with hippuric acid inhibited MPE and tumor growth, suggesting this metabolite may mediate some of the anti-tumor effects observed in C1q deficiency.
Disease outcome: C1q deficiency in macrophages suppressed MPE development and prolonged mouse survival . These findings demonstrate C1q is a key player in shaping macrophage phenotype and function in disease contexts.
What are the molecular mechanisms of C1q-mediated protein translation regulation in neurons?
The molecular mechanisms by which C1q regulates protein translation in neurons represent a significant recent discovery:
Ribosomal association: C1q physically associates with neuronal ribosomes in aging mouse brains . Immunostaining studies have visualized C1q infiltrating ribosomes, suggesting direct interaction with the protein synthesis machinery.
RNA-dependent interaction: This association is RNA-dependent, as demonstrated by the abolishment of ribosomal C1q signals following RNase treatment . This indicates RNA serves as a critical mediator for C1q's interaction with the translational apparatus.
Liquid-liquid phase separation: In vitro experiments have shown that C1q and RNA can form liquid droplets through liquid-liquid phase separation (LLPS) . This physicochemical property allows C1q to sequester RNA transcripts, potentially making them less available for translation.
Age-dependent effects: The mechanism appears age-regulated, with more pronounced effects in older animals. The researchers proposed that C1q interactions become "more gel-like" with age, excessively inhibiting translation .
Protein synthesis outcomes: Year-old mice lacking C1q produce proteins at a faster rate than wild-type mice, confirming C1q's role as a negative regulator of neuronal translation .
Potential disease relevance: Given C1q's elevation in Alzheimer's disease brains, its translation-inhibiting function may contribute to neuronal dysfunction in neurodegenerative conditions .
This newly discovered non-canonical function of C1q represents an important advance in understanding neuroimmune interactions and their impact on fundamental neuronal processes.
How can researchers effectively distinguish between beneficial and detrimental C1q activities in mouse models?
Distinguishing beneficial from detrimental C1q activities requires sophisticated experimental approaches:
Temporal manipulation: Using inducible genetic systems to delete or overexpress C1q at different developmental stages or ages can reveal time-dependent functions. This approach recognizes that C1q may be beneficial during development but harmful in aging or disease contexts.
Cell-type specific modulation: Conditional knockout strategies targeting C1q in specific cell populations (microglia, neurons, peripheral macrophages) can disentangle the cell-specific contributions to observed phenotypes .
Dose-dependent effects: Using heterozygous models or titrated interventions can reveal threshold effects, as moderate C1q activity may be beneficial while excessive activation becomes pathological.
Context-dependent evaluation: Comparing C1q's role across different disease models can identify context-specific functions. For example, C1q appears protective in stress-induced depression models but detrimental in certain cancer microenvironments .
Mechanism-specific targeting: Developing interventions that target specific C1q interactions (e.g., with neuronal ribosomes or with the CCR2-CCL2 signaling axis ) rather than global C1q activity may enable selective modulation of detrimental functions while preserving beneficial ones.
Combinatorial interventions: The study of malignant pleural effusion found that combining hippuric acid (elevated in C1q-deficient conditions) with CCR2 antagonists produced enhanced therapeutic effects compared to either treatment alone . This suggests targeting multiple C1q-associated pathways may be necessary to achieve optimal outcomes.
Product Science Overview
C1q is the recognition component of the C1 complex, which also includes the proteases C1r and C1s . When C1q binds to antibodies that are complexed with antigens, it triggers a cascade of events leading to the activation of the complement system . This activation results in the cleavage of C4 and C2, forming the C3/C5 convertase, which is essential for the downstream effects of the complement system .
Interestingly, C1q can also bind directly to the surface of certain pathogens, initiating the complement activation in the absence of antibodies . This ability highlights its role in innate immunity, providing a first line of defense against infections.
In mice, C1q is purified from pooled normal mouse serum and is a part of the C1 complex . The study of C1q in mice is crucial for understanding its role in immune responses and its potential implications in various diseases. Mice models are often used to study the genetic and molecular mechanisms of C1q, providing insights that can be translated to human health.
Research on C1q has revealed its involvement in various physiological and pathological processes. For instance, C1q has been linked to the clearance of apoptotic cells and the modulation of immune responses . Its deficiency or dysfunction can lead to autoimmune diseases, highlighting its importance in maintaining immune homeostasis .
