STMN4 Human
Description
Role in Neural Development
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Progenitor Maintenance: Prevents premature neurogenesis in the dorsal midbrain by prolonging the G₂ phase of neural progenitor cells .
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Compensatory Mechanisms:
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Microtubule Dynamics:
Retinal Development and Disease Links
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Copper Stress Response:
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Behavioral Defects: STMN4 mutants exhibit impaired touch response due to neural differentiation deficits .
Human Brain Expression Profile
Regional Specificity (Normalized RNA expression, nTPM) :
| Brain Region | Expression Level |
|---|---|
| Cerebral cortex | 15.2 |
| Hippocampus | 12.8 |
| Cerebellum | 9.4 |
| Midbrain | 8.1 |
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Single-Cell Enrichment: Highest in excitatory neurons and astrocytes .
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Evolutionary Conservation: Expression patterns conserved across mice, pigs, and humans .
Research Implications
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Therapeutic Targets: Potential role in neurodegenerative diseases via microtubule stability modulation.
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Developmental Biology: Essential for understanding neurogenesis timing and neural circuit formation.
Product Specs
Q&A
What is STMN4 and how does it relate to other Stathmin family proteins?
STMN4 is one of four proteins belonging to the Stathmin family of microtubule-binding proteins with functional roles in neuronal cytoskeletal regulation and axonal regeneration pathways. In humans, STMN1 and STMN3 transcripts exhibit ubiquitous expression, whereas STMN2 and STMN4 are enriched in CNS tissues . This tissue-specific expression pattern suggests specialized neural functions for STMN4 compared to its more broadly expressed family members.
What is the expression pattern of STMN4 during neural development?
Based on research in model organisms, STMN4 expression appears before neuronal differentiation in the developing brain. In zebrafish, stmn4 is first expressed in the dorsal midbrain region and ventral tegmentum during early development (around 11 hpf), with expression in the dorsal midbrain decreasing abruptly at later stages (24 hpf) . Importantly, the stmn4 expression domain is distinct from areas expressing neuronal markers such as elavl3 (HuC), suggesting STMN4 expression precedes terminal neuronal differentiation .
What cellular functions has STMN4 been implicated in?
Studies primarily in zebrafish demonstrate that STMN4 appears to inhibit neurogenesis and maintain neural progenitor pools. Knockdown of stmn4 in zebrafish causes precocious (premature) neuronal differentiation in the dorsal midbrain . This suggests STMN4 functions as a negative regulator of neuronal differentiation, playing a critical role in maintaining neural progenitor populations during brain development.
How does STMN4 mechanistically regulate neural progenitor maintenance?
While specific molecular mechanisms remain to be fully elucidated in humans, research suggests STMN4 likely regulates microtubule dynamics in neural progenitors. As a member of the Stathmin family, STMN4 presumably interacts with tubulin dimers and/or microtubules to influence cytoskeletal stability. The research in zebrafish demonstrates that when stmn4 is knocked down, neural progenitors prematurely differentiate into neurons , suggesting that STMN4-mediated cytoskeletal regulation may be necessary to maintain progenitor state. This could involve stabilizing cytoskeletal arrangements that support progenitor cell division or inhibiting cytoskeletal rearrangements needed for differentiation.
What is the relationship between STMN4 and neurological disease pathways?
Given the growing evidence for cytoskeletal defects in neurodegenerative diseases such as ALS , STMN4's role in microtubule regulation suggests potential involvement in disease mechanisms. While direct evidence linking STMN4 to neurological disorders is limited, its family member STMN2 has been implicated in ALS pathology through its regulation by TDP-43, an RNA-binding protein commonly mislocalized in ALS patients . Considering the functional similarities within the Stathmin family, STMN4 might similarly contribute to neurodegenerative processes through cytoskeletal dysregulation.
What are effective methods for studying STMN4 expression in human neural tissues?
Multiple complementary approaches are recommended for comprehensive analysis of STMN4 expression:
| Technique | Application | Advantages | Limitations |
|---|---|---|---|
| qRT-PCR | Quantitative expression analysis | High sensitivity, quantitative | No spatial information |
| In situ hybridization | Spatial expression mapping | Visualizes expression patterns in tissue context | Technically challenging in human samples |
| RNA-seq | Transcriptome-wide analysis | Unbiased, can detect splice variants | Requires bioinformatic expertise |
| Single-cell RNA-seq | Cell-type specific expression | Resolves heterogeneity in neural populations | Costly, may miss low-abundance transcripts |
| Immunohistochemistry | Protein-level spatial analysis | Detects protein in cellular context | Dependent on antibody specificity |
| Western blotting | Protein quantification | Semi-quantitative protein detection | No spatial information |
Combining these approaches provides comprehensive data on both the abundance and distribution of STMN4 across different neural cell types and developmental stages.
What genome editing strategies are most appropriate for functional STMN4 studies?
CRISPR-Cas9 genome editing offers several strategic approaches for investigating STMN4 function:
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Complete knockout: Generation of STMN4-null human iPSCs to differentiate into neural lineages for assessing neurodevelopmental phenotypes
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Domain-specific mutations: Introduction of specific mutations to identify functional domains critical for STMN4's role in neural progenitor maintenance
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Conditional systems: Implementation of inducible CRISPR systems for temporal control of STMN4 disruption at specific developmental stages
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Reporter knock-ins: Integration of fluorescent reporters at the STMN4 locus to monitor expression dynamics in living cells
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CRISPR screening: Development of guide RNA libraries targeting potential STMN4 regulators to identify upstream factors
When designing CRISPR experiments for STMN4, researchers should confirm editing efficiency through sequencing and assess potential compensation by other Stathmin family members, particularly STMN2 which shares neural expression patterns .
What model systems best recapitulate human STMN4 function?
A comparative model system approach is recommended:
| Model System | Advantages | Limitations | Application |
|---|---|---|---|
| Human iPSC-derived neural cells | Species-relevant, patient-specific models possible | Lacks organismal context | Molecular mechanisms, disease modeling |
| Brain organoids | 3D human neural tissue architecture | Variability between batches | Developmental studies, complex cell interactions |
| Zebrafish | Established stmn4 phenotypes, in vivo imaging | Evolutionary distance from humans | Rapid in vivo developmental analysis |
| Rodent models | Complex neural circuit analysis | Some divergence in expression patterns | Systems-level function, behavioral outcomes |
The zebrafish model has proven particularly valuable for STMN4 research, demonstrating that knockdown results in premature neuronal differentiation in the dorsal midbrain . This established phenotype provides a foundation for comparative studies in human models.
How might STMN4 dysfunction contribute to neurodevelopmental disorders?
STMN4 dysfunction could potentially contribute to neurodevelopmental disorders through several mechanisms:
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Premature depletion of neural progenitor pools due to reduced STMN4 function, resulting in abnormal neuronal numbers
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Disrupted timing of neurogenesis leading to improper lamination or regional development in the brain
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Cytoskeletal abnormalities affecting neuronal migration and circuit formation
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Potential interactions with known neurodevelopmental risk genes involved in cytoskeletal regulation
While direct evidence linking STMN4 to specific neurodevelopmental disorders is currently limited, its role in neural progenitor maintenance identified in model organisms suggests it could contribute to conditions characterized by abnormal brain development.
What approaches can detect altered STMN4 expression or function in patient samples?
Detecting STMN4 alterations in patients requires sensitive and specific methodologies:
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Genetic screening: Targeted sequencing of STMN4 and its regulatory regions in patient cohorts with relevant neurological phenotypes
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Brain tissue analysis: Examination of STMN4 expression in post-mortem brain samples from individuals with neurodevelopmental or neurodegenerative conditions
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Patient-derived cellular models: Generation of neural cells from patient iPSCs to assess STMN4 expression, localization, and function
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Proteomics: Mass spectrometry-based approaches to identify altered STMN4 protein levels or post-translational modifications
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Transcriptomics: RNA-seq analysis of patient-derived neural cells to identify altered STMN4 transcript levels or splicing patterns
The challenge with these approaches lies in the neural-specific expression of STMN4, which limits accessibility in most clinical samples outside of neural tissues.
What therapeutic strategies might target STMN4 pathways in neurological disorders?
Potential therapeutic strategies targeting STMN4 pathways depend on whether pathology stems from insufficient or excessive STMN4 activity:
| Pathological State | Therapeutic Approach | Mechanism | Development Considerations |
|---|---|---|---|
| Reduced STMN4 function | Gene therapy | AAV-mediated STMN4 delivery to neural progenitors | Requires precise temporal and spatial targeting |
| Reduced STMN4 function | Small molecule microtubule stabilizers | Mimicking STMN4's effects on cytoskeleton | Need neural-specific delivery to avoid systemic effects |
| Excessive STMN4 activity | Antisense oligonucleotides | Reducing STMN4 expression | Must establish specificity against other Stathmin family members |
| Downstream pathway dysfunction | Modulators of neural differentiation | Bypassing STMN4 to restore proper differentiation timing | Requires detailed understanding of downstream effectors |
Development of any STMN4-targeted therapy would require careful consideration of CNS-specific delivery and potential effects on other Stathmin family members.
What are the critical knowledge gaps in human STMN4 research?
Several critical knowledge gaps remain in our understanding of human STMN4:
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Comprehensive expression mapping across human brain development at single-cell resolution
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Molecular mechanisms by which STMN4 inhibits neuronal differentiation
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Potential roles in adult neurogenesis and neural repair processes
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Direct evidence for involvement in human neurological disorders
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Interactions with disease-associated proteins such as TDP-43, which regulates the related STMN2
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Functional differences between STMN4 and other neuronally-expressed Stathmin family members
Addressing these gaps will require integrated approaches combining human developmental tissue analysis, functional genomics, and detailed mechanistic studies in appropriate model systems.
How can emerging technologies advance STMN4 research?
Emerging technologies offer promising approaches to advance STMN4 research:
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Spatial transcriptomics to map STMN4 expression within complex brain tissues while preserving spatial context
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CRISPR-based epigenome editing to precisely manipulate STMN4 regulatory elements
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Advanced brain organoid models with region-specific patterning to study STMN4 in human neural development
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Live-cell super-resolution imaging to visualize STMN4-microtubule interactions in neural progenitors
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AI-driven analysis of neuroimaging and genetic data to identify associations between STMN4 variants and brain structure/function
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High-throughput phenotypic screening to identify compounds that modulate STMN4 function
Integration of these technologies with established approaches will enable more comprehensive understanding of STMN4's role in human neurobiology.
What collaborations would most advance the STMN4 research field?
Progress in STMN4 research would benefit from multidisciplinary collaborations bringing together:
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Developmental neurobiologists studying neural progenitor regulation
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Structural biologists elucidating STMN4-microtubule interactions
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Clinical researchers with access to relevant patient cohorts and samples
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Stem cell biologists developing advanced neural differentiation protocols
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Computational biologists for analysis of multi-omic data sets
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Experts in neurological disease mechanisms, particularly cytoskeletal-related disorders
Such collaborations would enable comprehensive investigation from molecular mechanisms to clinical relevance, accelerating progress in understanding this neural-specific regulator of development.
Product Science Overview
STMN4 is produced as a recombinant protein in Escherichia coli (E. coli). The recombinant human STMN4 is a single polypeptide chain consisting of 239 amino acids, with a molecular mass of approximately 27.8 kDa . The protein is fused to a 23 amino acid His-tag at the N-terminus, which facilitates its purification through proprietary chromatographic techniques .
STMN4 exhibits microtubule-destabilizing activity, similar to other members of the stathmin family. This activity is essential for the dynamic instability of microtubules, allowing them to rapidly grow and shrink. This dynamic behavior is critical for the proper functioning of the mitotic spindle during cell division, ensuring accurate chromosome segregation and cell cycle progression.
Recombinant human STMN4 is widely used in research to study its role in microtubule dynamics and its potential implications in various diseases. For instance, alterations in the expression or function of stathmin family proteins have been linked to cancer progression, neurodegenerative disorders, and other pathological conditions. By studying STMN4, researchers aim to gain insights into these diseases and develop potential therapeutic strategies.
The STMN4 solution is typically formulated in a buffer containing 20 mM Tris-HCl (pH 8.0), 0.2 M NaCl, 20% glycerol, and 1 mM DTT . For short-term storage, the protein can be kept at 4°C if used within 2-4 weeks. For long-term storage, it is recommended to store the protein at -20°C with the addition of a carrier protein such as 0.1% human serum albumin (HSA) or bovine serum albumin (BSA) to prevent degradation . It is important to avoid multiple freeze-thaw cycles to maintain the protein’s stability and activity.
