METRN Mouse

What is the difference between Meteorin (METRN) and Meteorin-like (Metrnl) in mice?

Meteorin (METRN) and Meteorin-like (Metrnl) are homologous secreted proteins with distinct expression patterns and functions. METRN is primarily expressed in the brain, particularly in Bergmann glia and discrete neuronal populations, with lower expression in astrocytes . In contrast, Metrnl shows a wider distribution throughout the body, with high expression in white adipose tissue and barrier tissues . Structurally, mouse Metrnl contains a post-translational N-glycosylation site that is not conserved in Metrn or human Metrnl, suggesting species-specific modifications . Functionally, METRN is predominantly involved in neural development and glial cell differentiation, while Metrnl plays roles in neural development, white adipose browning, insulin sensitization, and wound healing .

How is METRN expressed during mouse development and in adult tissues?

In adult mouse brain, METRN is highly expressed in Bergmann glia and specific neuronal populations, with low levels in astrocytes . During development, METRN expression is detected in undifferentiated neural and glial progenitors . For Metrnl, expression is notably elevated in white adipose tissue and barrier tissues . Expression patterns shift during physiological processes—for example, Metrnl expression significantly increases in mouse skin wound tissues during the healing process . This tissue-specific and context-dependent expression suggests specialized roles in different biological processes.

What are the known functions of METRN in mouse models?

METRN functions primarily as a neurotrophin involved in glial cell differentiation regulation . It generates glial cells with distinctive elongated "meteor-like" tails, hence its name . Metrnl, meanwhile, demonstrates multiple biological activities:

• Wound healing: Promotes skin wound healing through angiogenesis regulation

• Neural development: Required for neurite extension in neurons

• Metabolic regulation: Functions as an adipokine involved in white adipose browning and insulin sensitization

• Signal transduction: Activates AKT/eNOS signaling pathways in endothelial cells

These diverse functions position METRN and Metrnl as multifunctional regulators with tissue-specific effects.

What mouse models are available for studying METRN function?

Several genetically modified mouse models have been developed to study METRN and Metrnl functions:

These models enable tissue-specific and developmental analysis of METRN/Metrnl functions. The global knockout models are particularly valuable for identifying systemic effects, while conditional knockouts permit analysis of tissue-specific functions without developmental compensation mechanisms . When designing experiments, researchers should consider that complete ablation might trigger compensatory mechanisms that could mask phenotypes.

What antibodies and detection methods are available for METRN in mouse samples?

Several validated antibodies are available for detecting mouse METRN in experimental systems:

• Rat Anti-Mouse Meteorin Monoclonal Antibody (Clone #347504): Functions effectively as an ELISA detection antibody when paired with complementary capture antibodies .

• ELISA systems: Commercial DuoSet ELISA kits are available for quantitative measurement of mouse Meteorin in experimental samples .

For optimal detection in immunohistochemistry, western blotting, or ELISA applications, researchers should validate antibody specificity using appropriate controls. Detection of secreted METRN in conditioned media may require concentration steps due to potential dilution effects. When performing western blot analysis, researchers should consider the glycosylated forms of Metrnl, which appear at approximately 34 kDa, with deglycosylated forms appearing closer to the calculated mass of 30 kDa .

How can researchers effectively isolate and purify recombinant METRN for functional studies?

For functional studies requiring purified METRN, researchers can express C-terminally His-tagged versions of mouse METRN in eukaryotic expression systems such as HEK293, COS-7, or HEK293F cells . The secreted protein can be purified from serum-free conditioned media using affinity chromatography. MALDI-TOF MS analysis has shown mouse Metrnl to have a mass of approximately 33.8 kDa with a shoulder at 33.4 kDa, reflecting glycosylated forms .

For deglycosylation analysis, treating the purified protein with glycopeptidase F or N-glycanase results in a single band of reduced molecular weight, confirming post-translational glycosylation . When designing functional experiments, researchers should consider whether native glycosylation is required for biological activity, as the N-glycosylation site in mouse Metrnl is not conserved in human Metrnl .

How does Metrnl affect skin wound healing in mice?

Metrnl plays a critical role in promoting skin wound healing through angiogenesis regulation. Studies using 8-mm diameter full-thickness excisional wounds in mice demonstrate that both global (Metrnl^(-/-)) and endothelial cell-specific (EC-Metrnl^(-/-)) Metrnl gene knockout significantly retard wound healing . Mechanistically, endothelial Metrnl appears to be the key factor affecting wound healing and angiogenesis, with expression levels markedly increased in skin wound tissues during the healing process .

The impaired wound healing in Metrnl-deficient mice correlates with reduced angiogenesis at wound sites. Quantitative analysis of wound closure rates shows significant delays in both knockout models compared to wild-type controls, with endothelial-specific knockout demonstrating the most pronounced effects .

What molecular mechanisms underlie Metrnl's effects on angiogenesis?

Metrnl regulates angiogenesis through multiple molecular mechanisms:

• Endothelial cell function: Metrnl knockdown inhibits proliferation, migration, and tube formation in human umbilical vein endothelial cells (HUVECs), while addition of recombinant Metrnl (10 ng/mL) significantly promotes these activities .

• VEGFA signaling: Metrnl deficiency abolishes VEGFA-stimulated (10 ng/mL) endothelial cell proliferation but does not affect bFGF-stimulated (10 ng/mL) proliferation, suggesting a VEGFA-specific pathway interaction .

• AKT/eNOS activation: Metrnl deficiency impairs VEGFA downstream AKT/eNOS activation both in vitro and in vivo. This impairment can be partially rescued by addition of the AKT activator SC79 (10 μM) .

These findings establish a mechanistic pathway where Metrnl functions as a critical mediator of VEGFA-dependent angiogenesis through the AKT/eNOS signaling axis, providing a molecular explanation for its wound healing effects.

What is the role of METRN in neurite extension and neural development?

METRN functions as a neurotrophin with critical roles in neurite extension during neural development. Both METRN and Metrnl are implicated in these processes, with Metrnl identified as a latent process (LP) gene whose expression is upregulated during preparatory steps for cellular function and is required for subsequent neurite extension .

Experimental evidence demonstrates that small interfering RNA targeting Metrnl significantly inhibits NGF-induced neurite extension in PC12 cells (an adrenal chromaffin cell line used as a neural model) . This inhibition can be partially prevented by Metrnl rescue constructs, indicating an indispensable role in neurite development. The effect has been confirmed in primary dissociated hippocampal neurons of rats, demonstrating consistency between cell lines and primary neurons .

How does METRN expression relate to ERK signaling in neural cells?

Metrnl expression in neural cells is dependent on ERK activity, which is significant because persistent ERK activation is required for NGF-induced differentiation of PC12 cells . This positions Metrnl as a downstream effector in the ERK signaling cascade that regulates neuronal differentiation and neurite extension.

For researchers studying neural development, these findings suggest that modulating METRN/Metrnl levels could provide a means to regulate neurite extension and neuronal differentiation. When designing experiments to study these processes, consideration should be given to the temporal aspects of METRN expression and activation, as its classification as a latent process gene indicates its role in preparatory phases of neural development.

How do METRN and Metrnl functions differ between mice and humans?

Comparative analysis between mouse and human METRN/Metrnl reveals important differences that researchers should consider when translating findings:

• Glycosylation patterns: The N-glycosylation site present in mouse Metrnl is not conserved in human Metrnl or mouse METRN , suggesting species-specific post-translational modifications that may affect protein function or stability.

• Expression patterns: While general tissue distribution patterns are similar, the relative expression levels and precise cellular localization may differ between species, potentially leading to functional differences.

• Structural homology: Despite differences in post-translational modifications, the core protein structures show significant conservation, suggesting fundamental functional similarities.

When designing translational studies, researchers should validate findings in human cell systems or tissues to confirm conservation of mechanisms identified in mouse models. Particular attention should be paid to species-specific interaction partners that might affect signaling outcomes.

What are the technical challenges in studying METRN secretion and function?

Researchers face several methodological challenges when investigating METRN:

• Protein detection sensitivity: As a secreted protein that may be present at low concentrations in biological fluids, sensitive detection methods are essential. Optimized ELISA protocols with appropriate antibody pairs are recommended .

• Functional redundancy: Potential redundancy between METRN and Metrnl may mask phenotypes in single knockout models. Consider double knockout approaches or domain-specific mutations to address this issue.

• Tissue-specific effects: Given the diverse functions across tissues, cell-type specific conditional knockouts provide more precise insights than global deletion models.

• Temporal dynamics: Since METRN functions may be developmentally regulated or acute-phase responsive (as in wound healing), time-course studies with appropriate sampling intervals are crucial.

How can researchers resolve contradictory findings about METRN functions across different experimental systems?

When faced with seemingly contradictory results regarding METRN functions, researchers should systematically address potential sources of variation:

• Protein isoforms: Verify which splice variants or post-translationally modified forms are present in different experimental systems, as the mouse METRN gene has 6 transcripts (splice variants) .

• Dosage effects: Establish dose-response relationships, as METRN may have concentration-dependent effects, particularly in signaling contexts.

• Context dependency: Evaluate environmental factors like growth media composition, oxygen levels, or matrix components that might influence METRN function.

• Genetic background: Consider mouse strain differences, as genetic modifiers may influence METRN phenotypes.

• Methodology standardization: Employ standardized protocols for protein production, purification, and functional assays to facilitate cross-laboratory comparisons.

What are the most promising future research directions for METRN in mouse models?

Based on current knowledge, several high-priority research directions emerge:

• Tissue-specific conditional knockouts: Further development of conditional knockout models targeting specific cell types beyond endothelial cells could elucidate cell-autonomous functions.

• Receptor identification: Definitive identification of METRN and Metrnl receptors remains a critical gap in understanding signaling mechanisms.

• Therapeutic applications: Mouse models of wound healing, metabolic disorders, and neurological conditions provide platforms to evaluate therapeutic potential of recombinant METRN or Metrnl.

• Integration with other pathways: Exploring crosstalk between METRN signaling and other established pathways (e.g., Wnt, Notch) could reveal broader regulatory networks.

• Single-cell approaches: Applying single-cell transcriptomics to METRN-expressing tissues could reveal cellular heterogeneity and identify new target cell populations.