SERPINE2 Mouse

What is SERPINE2 and what are its primary functions in mouse physiology?

SERPINE2 is a member of the serine protease inhibitor superfamily, expressed in numerous organs and tissues. It functions as a potent endogenous thrombin inhibitor primarily found in the extracellular matrix and platelets. Its multiple functions are mediated through regulating urokinase-type plasminogen activator (uPA/PLAU), tissue-type plasminogen activator (tPA/PLAT), and matrix metalloproteinase activity . SERPINE2 plays crucial roles in hemostasis, cell adhesion, cochlear hair cell regeneration, and reproductive processes .

What alternative nomenclature is used for SERPINE2 in scientific literature?

SERPINE2 appears in scientific literature under various designations including: Serpin E2, PN-1, PI-7, PN1, Protease nexin I, PNI, Protease nexin 1, GDNPF, Peptidase inhibitor 7, Glia-derived nexin, GDN, and PI7 . Researchers should be aware of these alternative designations when conducting literature searches to ensure comprehensive coverage of available research.

How does SERPINE2 expression change during mouse development?

SERPINE2 expression in the mouse cochlea follows a downward trend as mice age after birth . This developmental expression pattern suggests SERPINE2 has temporally regulated functions, potentially explaining why certain regenerative capacities diminish with age. Understanding this temporal regulation is crucial for designing age-appropriate interventions in mouse models.

What techniques are available for quantifying SERPINE2 in mouse experimental samples?

SERPINE2 can be quantified using Enzyme-Linked Immunosorbent Assay (ELISA) techniques. Commercial kits such as the Mouse SERPINE2 ELISA Kit (ARG82410) enable precise quantification in serum, plasma (EDTA, heparin, citrate), cell culture supernatants, and urine . This kit offers a sensitivity of 0.39 ng/ml with a standard range of 0.78-50 ng/ml, requiring only 100 μl sample volume . Researchers should consider precision metrics (Intra-Assay CV: 5.3%, Inter-Assay CV: 6.5%) when designing experiments .

What methodological considerations are important when analyzing SERPINE2 in reproductive tissues?

When analyzing SERPINE2 in reproductive tissues, researchers have successfully employed liquid chromatography coupled with tandem mass spectrometry for identification and characterization . This approach allowed researchers to purify SERPINE2 from mouse seminal vesicle secretion and confirm its inhibitory activity against urokinase-type plasminogen activator . For tissue-specific localization, immunohistochemical analysis has been effective for detecting SERPINE2 in testicular cells (spermatogonia, spermatocytes, spermatids, Leydig cells) and on the acrosomal cap of sperm .

How can researchers effectively manipulate SERPINE2 expression in mouse models?

Based on recent studies, successful approaches include:

What is the mechanism by which SERPINE2 promotes hair cell regeneration?

SERPINE2 plays a pivotal role in hair cell regeneration from Lgr5+ progenitors in the neonatal mouse cochlea through several molecular pathways . Single-nucleus RNA sequencing and mRNA validation reveal that conditionally overexpressed SERPINE2 induces hair cell regeneration primarily by:

• Inhibiting the sonic hedgehog (SHH) signaling pathway

• Inducing expression of Atoh1 and Pou4f3 transcription factors, which are essential for hair cell development

This mechanism provides a potential therapeutic target for sensorineural hearing loss, which is primarily caused by loss of or damage to cochlear hair cells.

Does SERPINE2-mediated hair cell regeneration occur via mitotic regeneration or direct transdifferentiation?

EdU assay and lineage tracing experiments demonstrate that the ectopic hair cells resulting from SERPINE2 overexpression likely originate from Lgr5+ progenitors through direct transdifferentiation rather than through mitotic regeneration . This finding has significant implications for understanding the fundamental mechanisms of inner ear regenerative biology and for developing targeted regenerative therapies.

How does the dose of SERPINE2 affect hair cell regeneration outcomes?

Conditional overexpression of SERPINE2 in Lgr5+ progenitors of neonatal mice cochlea results in an increased number of ectopic hair cells in a dose-dependent manner . This dose-dependency suggests that precise regulation of SERPINE2 levels is critical for optimal regenerative outcomes. Researchers should carefully titrate SERPINE2 expression or application when designing regenerative interventions.

What is the distribution of SERPINE2 in male mouse reproductive tissues?

SERPINE2 shows a distinct distribution pattern across male reproductive tissues:

This distribution pattern suggests tissue-specific functions throughout the male reproductive tract .

How does SERPINE2 influence sperm capacitation and fertility in mice?

SERPINE2 functions as a sperm decapacitation factor in mice. It is detected on uncapacitated sperm but absent on capacitated sperm, indicating its loss during the capacitation process . Experimental evidence shows that SERPINE2:

• Inhibits BSA-induced sperm capacitation in vitro

• Prevents sperm binding to eggs, thus blocking fertilization

• Acts by preventing cholesterol efflux from sperm membranes, one of the initiation events of capacitation

Importantly, SERPINE2 can reversibly regulate mouse sperm from capacitation to non-capacitation both in vivo and in vitro, suggesting potential applications in fertility control .

What are the consequences of SERPINE2 deficiency on male fertility?

Deletion of the SERPINE2 gene leads to infertility in male mice . This finding underscores the critical role of plasminogen-plasmin system homeostasis in semen for reproductive function. The exact mechanisms linking SERPINE2 deficiency to infertility likely involve dysregulation of proteolytic processes essential for normal sperm function and fertilization capacity.

How does SERPINE2 interact with the Sonic Hedgehog (SHH) signaling pathway in neural development?

SERPINE2 inhibits SHH-induced proliferation of cerebellar granular neuron precursors (CGNPs) during mouse cerebellum development . This inhibition reduces the subsequent increase in mature cerebellar cells, making the interaction between SERPINE2 and SHH crucial for proper cerebellar development . Beyond normal development, in Alzheimer's disease (AD) mice, SERPINE2 (PN-1) can inhibit activation of the SHH pathway, potentially affecting disease progression .

What neurological functions are affected by SERPINE2 deficiency in mice?

SERPINE2 deficiency affects multiple brain regions and functions:

• Alters hippocampal function

• Modifies amygdala responses responsible for emotional processing (fear, anxiety) and memory

• Reduces fear extinction capabilities (evidenced by lower Fos immunoreactivity in the basal ganglia of SERPINE2-defective mice compared to wild-type mice)

These findings suggest SERPINE2 as a potential therapeutic target for anxiety and stress-related disorders.

What neuroprotective functions does SERPINE2 exhibit in mouse models?

As a potent thrombin inhibitor, SERPINE2 is crucial for inhibiting thrombin-mediated ischemic neuronal death in the central nervous system . This neuroprotective function positions SERPINE2 as a potential intervention target for ischemic brain injuries and stroke. Researchers investigating neuroprotective agents should consider SERPINE2's role in thrombin regulation when designing experimental models.

What methodological challenges exist in studying SERPINE2 function across different tissues?

Several methodological challenges complicate SERPINE2 research:

• Temporal expression patterns that change with development and aging

• Multiple functions across diverse tissues requiring tissue-specific experimental designs

• Complex interactions with extracellular matrix components and multiple signaling pathways

• The need for conditional and cell-type specific manipulation to avoid confounding systemic effects

Researchers should implement tissue-specific conditional expression systems and careful temporal controls in experimental designs.

How can apparent contradictions in SERPINE2 function be reconciled?

SERPINE2 exhibits seemingly contradictory functions in different contexts. For example, it inhibits proliferation in cerebellar development through SHH pathway inhibition , yet promotes regeneration in cochlear hair cells (also involving SHH pathway modulation) . These apparent contradictions likely reflect:

• Tissue-specific contexts and co-regulators

• Developmental stage dependencies

• Concentration-dependent effects

• Interactions with tissue-specific extracellular matrix components

Researchers should design experiments that specifically address these contextual differences to resolve apparent contradictions.

What are promising translational applications for SERPINE2 research in mouse models?

Several translational directions emerge from current SERPINE2 research:

• Hair cell regeneration therapies for sensorineural hearing loss

• Fertility regulation, with potential applications in contraception and assisted reproductive technologies

• Treatments for anxiety and stress-related disorders targeting SERPINE2 in the amygdala

• Interventions for Alzheimer's disease through modulation of SERPINE2's interaction with the SHH pathway

• Neuroprotective strategies for ischemic brain injuries leveraging SERPINE2's thrombin inhibitory activity

Future research should focus on optimizing delivery methods, timing, and dosing for these potential therapeutic applications.