OLFM1 Human
Description
Molecular Structure and Isoforms
OLFM1 belongs to the olfactomedin-domain protein family, characterized by a conserved C-terminal olfactomedin domain . The human OLFM1 gene (chromosome 9q34.3) produces multiple isoforms through alternative splicing:
| Isoform | Length (aa) | Key Features | Secretion Status |
|---|---|---|---|
| AMZ/BMZ | 457–485 | Contains olfactomedin domain | Limited secretion |
| AMY/BMY | 125–153 | Lacks olfactomedin domain | Robustly secreted |
The longer isoforms (AMZ/BMZ) form dimers and oligomers via cysteine residues in their central region, while shorter isoforms (AMY/BMY) are implicated in intracellular signaling .
Expression Patterns
OLFM1 exhibits tissue-specific expression:
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Nervous System: Abundant in the cerebral cortex, hippocampus, and retina .
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Developmental Tissues: Detected in embryonic heart and neural crest cells .
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Cancer: Overexpressed in human papillomavirus (HPV)-associated cervical preneoplastic lesions .
Single-cell RNA sequencing highlights OLFM1 expression in myeloid lineage cells and retinal ganglion cells .
Neural Development and Axon Growth
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NgR1 Interaction: OLFM1 binds to the Nogo A receptor (NgR1), inhibiting its interaction with coreceptors (p75NTR, LINGO-1) to promote axon regeneration .
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Neurogenesis: Regulates neural crest formation in vertebrates and optic nerve arborization in zebrafish .
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Cell Adhesion: Modulates E-cadherin (Cdh1) expression and Snail1/Mitf-a pathways, affecting epithelial-mesenchymal transitions .
Disease Associations
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Ischemic Stroke: OLFM1 knockout mice show reduced cerebral infarction size, implicating it in neuronal apoptosis .
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Cancer: Overexpression correlates with cervical cancer progression and myeloid differentiation .
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Glaucoma: Indirectly linked via interaction with OLFM3 (Optimedin) in trabecular meshwork cells .
Key Pathways
Genetic Knockdown Effects
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Zebrafish: Morpholino-induced OLFM1 suppression causes brain/eye defects, rescued by mouse OLFM1 RNA .
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Mice: Olfm1 deletion reduces body weight and impairs embryo implantation .
Clinical and Therapeutic Implications
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Biomarker Potential: OLFM1’s overexpression in cervical lesions and myeloid cells positions it as a prognostic marker .
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Neural Repair: Targeting OLFM1-NgR1 interactions could enhance axon regeneration post-injury .
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Cancer Therapy: Modulation of OLFM4 (a homolog) in intestinal stem cells suggests parallel strategies for OLFM1 .
Unresolved Questions
Product Specs
Q&A
What are the primary biological functions of OLFM1 in humans?
OLFM1 regulates neural development and synaptic plasticity by interacting with receptors such as NgR1 (Nogo A receptor) and amyloid precursor protein (APP). Structural studies reveal its role in trans-synaptic tethering, where oligomeric states (monomer, dimer, tetramer) dictate binding avidity to synaptic partners . For example, tetrameric OLFM1 enhances AMPA receptor clustering at postsynaptic membranes, while monomeric forms disrupt NgR1-p75NTR/LINGO-1 interactions to promote axon regeneration . Methodologically, confirming these roles requires:
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Co-immunoprecipitation (Co-IP) to identify binding partners (e.g., NgR1) .
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CRISPR/Cas9 knockout models to assess synaptic morphology changes .
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Small-angle X-ray scattering (SAXS) to characterize oligomer-dependent receptor clustering .
How is OLFM1 expression regulated across tissues?
OLFM1 is highly expressed in the brain (olfactory bulb, hippocampus, cortex) and reproductive organs. RNA-seq data from the Allen Brain Atlas shows dynamic expression during prenatal development, peaking in early neurogenesis . To map expression:
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Single-cell RNA sequencing identifies cell-type-specific expression (e.g., mitral cells in the accessory olfactory bulb) .
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Immunohistochemistry localizes OLFM1 isoforms in human postmortem tissues .
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Promoter analysis of alternative transcripts (A1/A2 and C1/C2 splice variants) reveals tissue-specific regulatory elements .
How does OLFM1 influence aging trajectories and disease risk?
OLFM1 is implicated in organ-specific aging signatures. Plasma proteomics studies link elevated OLFM1 levels to accelerated brain aging (β = 0.34, p < 0.001) and Alzheimer’s disease progression, independent of pTau-181 . Mendelian randomization suggests OLFM1’s detrimental effect on healthspan (OR: 1.22, 95% CI: 1.07–1.39) . Key methodologies include:
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Proteome-wide MR analysis to infer causal relationships between OLFM1 and aging .
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Organ aging clocks trained on 11 organ systems to quantify OLFM1-associated mortality risk .
Table 1: OLFM1-Associated Aging Phenotypes
| Phenotype | Study Design | Effect Size | Citation |
|---|---|---|---|
| Cognitive decline | Longitudinal cohort | HR = 2.1 | |
| Cardiovascular aging | Proteomic MR | OR = 1.45 | |
| Frailty index | GWAS meta-analysis | β = -0.18 |
What experimental models resolve contradictions in OLFM1’s role in fertility?
While Olfm1−/− female mice exhibit 41% reduced cFos activation in accessory olfactory bulbs and impaired estrous cyclicity , human studies lack direct evidence. To reconcile this:
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Conditional knockout models (e.g., hypothalamic-specific deletion) isolate reproductive vs. olfactory deficits.
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Human organoid systems model GnRH neuron development under OLFM1 inhibition .
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Cross-species proteomics compares OLFM1 interactomes in murine vs. human gonadotropes .
How do OLFM1 structural variants affect synaptic receptor clustering?
The C-terminal β-propeller domain of OLFM1 contains a hydrophilic tunnel that coordinates Ca²⁺/Na⁺ ions, modulating APP binding . Truncation mutants (Δβ-propeller) fail to rescue AMPA receptor clustering in Olfm1−/− neurons. Key approaches:
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X-ray crystallography resolves ion-binding sites (PDB: 8OLF) .
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Electrophysiology assays quantify AMPA-mediated currents in OLFM1-variant-expressing neurons .
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Molecular dynamics simulations predict oligomer-dependent binding kinetics .
How to address OLFM1’s pleiotropic effects in disease association studies?
OLFM1 associates with schizophrenia (via DISC1 interaction) , heart failure , and osteoarthritis . Disentangling causality requires:
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Colocalization analysis (e.g., FINEMAP) to distinguish OLFM1-specific loci from linkage disequilibrium .
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Cell-type-specific MR using snRNA-seq-derived expression weights .
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Perturb-seq screens to identify OLFM1-dependent transcriptional modules.
What strategies validate OLFM1 as a therapeutic target for axon regeneration?
OLFM1 inhibits NgR1 signaling by competing with p75NTR (IC₅₀ = 12 nM) . Preclinical validation involves:
Product Science Overview
Olfactomedin 1 was first identified in the olfactory neuroepithelium of the bullfrog, where it was found to be secreted into the nasal lumen and associated with chemosensory dendritic cilia . The protein forms disulfide-linked aggregates and is believed to serve as a differentiation signal for chemosensory neurons .
Structurally, Olfactomedin 1 exists in multiple isoforms due to alternative promoter usage and splicing . These isoforms, referred to as AMY, BMY, AMZ, and BMZ, are differentially expressed in various brain regions and during different developmental stages . The long isoform BMZ forms a disulfide-linked tetramer with a V-shaped architecture, where each tip of the “V” consists of two C-terminal β-propeller domains enclosing a calcium-binding site .
Olfactomedin 1 is highly expressed in the brain and retina, indicating its significant role in nervous system development and function . The protein is involved in various processes, including:
- Synaptic Function: Olfactomedin 1 is believed to play a role in the tethering or clustering of synaptic receptors, such as post-synaptic AMPA receptors and pre-synaptic amyloid precursor protein .
- Cell Adhesion and Interaction: The olfactomedin domain facilitates protein-protein interactions and intercellular adhesion, which are critical for the organization of the nervous system .
- Neurodevelopment: Olfactomedin 1 is implicated in the differentiation and development of neurons, particularly in the olfactory system .
Human recombinant Olfactomedin 1 is produced using recombinant DNA technology, which involves inserting the OLFM1 gene into an expression system, such as bacteria or mammalian cells, to produce the protein in large quantities. This recombinant protein can be used for various research purposes, including structural and functional studies .
Research on Olfactomedin 1 has provided insights into its structural and functional properties, which are essential for understanding its role in the nervous system . The protein’s involvement in synaptic function and cell adhesion makes it a potential target for studying neurological disorders and developing therapeutic interventions .
In conclusion, Olfactomedin 1 is a critical protein in the nervous system, with diverse roles in synaptic function, cell adhesion, and neurodevelopment. The recombinant production of this protein enables further research into its functions and potential clinical applications.
