MESDC1 Human

What is MESDC1 and where is it located in the human genome?

MESDC1 (Mesoderm Development Candidate 1) is a 362 amino acid protein encoded by a gene that maps to human chromosome 15q25.1. It is also known by the synonym TLNRD1 and is a member of the MESD family. The protein is identified by the UniProt designation MESD1_HUMAN . Chromosome 15, where MESDC1 is located, comprises approximately 106 million base pairs and represents about 3% of the human genome, encoding more than 700 genes . The MESDC1 gene has the NCBI Gene ID 59274 .

What is the general function of MESDC1 in human cells?

MESDC1 primarily functions as a chaperone for low-density lipoprotein receptors . While detailed functional characterization remains ongoing, current research indicates it plays a role in protein trafficking and may be involved in regulation of signaling pathways. MESDC1 has documented functional associations with 3,289 biological entities spanning 7 categories, including molecular profiles, functional terms, chemicals, diseases, phenotypes, cell lines, and other genes and proteins . These associations suggest MESDC1 participates in complex cellular networks that may impact development and signaling.

What is the expression pattern of MESDC1 across human tissues?

MESDC1 expression has been profiled across multiple tissues through various datasets. Significant expression data is available from the Allen Brain Atlas collections, which document MESDC1 expression in:

• Adult human brain tissues

• Adult mouse brain tissues

• Developing human brain tissues (via both microarray and RNA-seq approaches)

• Prenatal human brain tissues

Additional expression data is available through BioGPS Human Cell Type and Tissue Gene Expression Profiles, indicating MESDC1 has distinct expression patterns across different cell and tissue types . This tissue-specific expression pattern may provide insights into its context-dependent functions.

What are effective methods for knocking down MESDC1 expression in experimental models?

For MESDC1 knockdown experiments, siRNA approaches have been well-documented. Commercial reagents such as MESDC1 siRNA are available and have been used successfully in mammalian models . For more complete knockout studies, CRISPR-Cas9 genome editing has proved effective, as demonstrated in studies using mouse embryonic stem cells (mESCs) that were subsequently differentiated into neural progenitor cells .

The selection of methodology should consider:

• Duration of knockdown required (transient vs. stable)

• Cell type-specific transfection efficiency

• Potential off-target effects

• Whether partial (knockdown) or complete (knockout) loss of function is desired

When implementing either approach, validation of MESDC1 reduction should be performed at both mRNA (via qRT-PCR) and protein levels (via Western blot) to confirm successful targeting.

How can researchers effectively detect and quantify MESDC1 protein in experimental samples?

Detection and quantification of MESDC1 can be accomplished through several complementary approaches:

• Western Blotting: Using specific antibodies against MESDC1 (anti-MESDC1/TLNRD1) for semi-quantitative detection in cell or tissue lysates

• Immunohistochemistry (IHC): For visualization of MESDC1 expression patterns in tissue sections

• Immunofluorescence: For subcellular localization studies and co-localization with potential interacting partners

• Mass Spectrometry: For precise quantification and identification of post-translational modifications

For detection of recombinant MESDC1, commercially available human recombinant MESDC1 protein can serve as a positive control (catalog number PRO-1950) . Researchers should validate antibody specificity using appropriate positive and negative controls, particularly when examining tissues with expected low expression levels.

What are the methodological considerations for studying MESDC1 interactions with other proteins?

To investigate MESDC1 protein interactions, researchers can employ multiple complementary techniques:

• Co-immunoprecipitation (Co-IP): To identify native protein complexes containing MESDC1

• Proximity Ligation Assays (PLA): For detecting protein-protein interactions in situ with high sensitivity

• Yeast Two-Hybrid Screening: For systematic identification of potential binding partners

• Pull-down Assays: Using tagged recombinant MESDC1 to capture interacting proteins

• BioID or APEX Proximity Labeling: For capturing transient or weak interactions within the cellular context

When designing these experiments, researchers should consider that MESDC1's function as a chaperone for low-density lipoprotein receptors suggests interactions may be transient or context-dependent. Controls should include verification that antibody-based techniques do not interfere with binding interfaces and that tagging strategies do not disrupt protein folding or function.

How does MESDC1 contribute to mesoderm development?

While the name "Mesoderm Development Candidate 1" suggests a role in mesoderm formation, detailed mechanistic studies specifically linking MESDC1 to mesoderm development remain limited. The initial identification of MESDC1 as a mesoderm development candidate gene was accomplished through comparative mapping and genome sequence analysis approaches .

The related family member MESD (also known as MESDC2) has been more extensively characterized and has been shown to modulate LRP6-mediated Wnt signaling . By analogy, MESDC1 may have a role in developmental signaling pathways, potentially through its chaperone function. Researchers investigating MESDC1's role in development should consider:

• Temporal expression patterns during embryogenesis, particularly during mesoderm specification and differentiation

• Potential interactions with developmental signaling pathways, especially Wnt signaling components

• Phenotypic consequences of MESDC1 loss-of-function in developmental model systems

What is the relationship between MESDC1 and Wnt signaling pathways?

While direct evidence for MESDC1's role in Wnt signaling is limited in the provided references, there are indications of a potential connection. The related protein MESD (MESDC2) has been demonstrated to modulate LRP6-mediated Wnt signaling as a molecular chaperone . Given that MESDC1 also functions as a chaperone for low-density lipoprotein receptors , and LRP6 is a member of the low-density lipoprotein receptor family, MESDC1 may have similar or complementary functions in Wnt pathway regulation.

To investigate this relationship, researchers might:

• Assess changes in Wnt signaling activity following MESDC1 knockdown or overexpression

• Examine direct interactions between MESDC1 and Wnt pathway components, particularly LRP family members

• Evaluate whether MESDC1 affects subcellular localization or stability of Wnt receptors

• Determine if MESDC1 expression is regulated by Wnt pathway activation

Understanding this potential relationship could provide insights into how MESDC1 might influence developmental processes and signaling networks.

How can eQTL analysis contribute to understanding MESDC1 function and regulation?

Expression Quantitative Trait Loci (eQTL) analysis represents a powerful approach to understanding the genetic basis of MESDC1 expression variation. eQTL studies identify genetic variants that influence gene expression levels, providing insights into regulatory mechanisms and potential functional implications.

Methodologically, researchers can conduct eQTL analysis for MESDC1 by:

• Analyzing associations between SNPs and MESDC1 expression levels in relevant tissues

• Distinguishing between cis-eQTLs (variants within 250kb of the gene) and trans-eQTLs (variants >5Mb away)

• Applying appropriate statistical methods to control for multiple testing, including False Discovery Rate (FDR) procedures

• Correcting for population stratification effects using multidimensional scaling vectors as covariates

When interpreting eQTL results for MESDC1, researchers should consider:

• Tissue specificity of identified eQTLs

• Potential functional consequences of expression variation

• Integration with other genomic data types, such as epigenetic marks and chromatin accessibility

• Possible links between identified eQTLs and disease-associated variants

What approaches can be used to study MESDC1's role in developmental disorders associated with chromosome 15?

Chromosome 15, where MESDC1 is located (15q25.1), is associated with several developmental disorders, including Angelman syndrome, Prader-Willi syndrome, and others . While these syndromes primarily involve genes in the 15q11-q13 region rather than MESDC1 directly, investigating potential contributions of MESDC1 to developmental processes might provide broader insights.

Research approaches could include:

• Case-Control Association Studies: Examining potential MESDC1 variants in patients with developmental disorders

• Expression Analysis: Comparing MESDC1 expression in affected vs. unaffected tissues in relevant disorders

• Functional Genomics: Using CRISPR-based screens in developmental model systems to assess interactions between MESDC1 and known disease-associated genes

• Animal Models: Generating and characterizing MESDC1 mutant models to assess developmental phenotypes

When conducting such studies, researchers should carefully consider:

• The specific chromosomal location of MESDC1 (15q25.1) relative to known disease-associated regions

• Potential long-range regulatory interactions affecting MESDC1 expression

• Tissue-specific expression patterns during development

• Possible genetic interactions with other chromosome 15 genes

How might CRISPR screening approaches be applied to elucidate MESDC1 function in different cellular contexts?

CRISPR-based functional genomics represents a powerful approach for investigating MESDC1's role in different biological contexts. As demonstrated in previous studies, CRISPR screens can effectively identify genes involved in morphogen signal interpretation and cellular responses .

To apply CRISPR screening specifically to MESDC1 research:

• Forward Genetic Screens:

  • Design CRISPR libraries targeting genes potentially interacting with MESDC1

  • Use fluorescent reporters to select for cells with phenotypes of interest

  • Sequence guide RNAs enriched in selected populations to identify genetic modifiers

• Synthetic Lethality Screens:

  • Generate MESDC1-knockout cell lines

  • Perform genome-wide CRISPR screens to identify genes whose loss is specifically lethal in MESDC1-deficient backgrounds

  • Validate hits to map genetic interaction networks

• Domain-Focused Screens:

  • Apply CRISPR base editing or prime editing to introduce specific mutations in functional domains of MESDC1

  • Assess functional consequences to map structure-function relationships

As demonstrated in neural progenitor cell models, CRISPR-based gene knockout approaches can be particularly valuable for studying developmental signaling pathways in physiologically relevant contexts . Researchers should consider using cell types where MESDC1 is endogenously expressed at meaningful levels based on expression databases .

How does MESDC1 expression vary across neural tissues and developmental stages?

Based on comprehensive expression data from the Allen Brain Atlas collections, MESDC1 shows distinct expression patterns across neural tissues and developmental stages. These datasets provide valuable reference points for researchers investigating MESDC1's role in neural development and function:

• Adult Human Brain Tissue Gene Expression Profiles

• Adult Mouse Brain Tissue Gene Expression Profiles

• Developing Human Brain Tissue Gene Expression Profiles (both microarray and RNA-seq data)

• Prenatal Human Brain Tissue Gene Expression Profiles

When analyzing MESDC1 expression, researchers should consider:

• Regional specificity within the nervous system

• Temporal dynamics during development

• Correlation with developmental processes such as neurogenesis, migration, or synaptogenesis

• Comparison with expression patterns of functionally related genes

This expression data can guide the selection of appropriate model systems and developmental timepoints for functional studies of MESDC1 in neural contexts.

What are the technical considerations for purifying recombinant MESDC1 protein for biochemical studies?

For researchers requiring purified MESDC1 protein for biochemical and structural studies, several technical considerations should be addressed:

• Expression Systems:

  • Mammalian expression systems may best preserve post-translational modifications and proper folding

  • Bacterial systems offer high yield but may require refolding protocols

  • Insect cell systems represent a compromise between yield and proper folding

• Purification Tags:

  • N-terminal vs. C-terminal tag placement should be evaluated for effects on folding and function

  • Cleavable tags are preferable for structural studies

  • Common options include His-tag, GST, MBP (the latter two potentially enhancing solubility)

• Buffer Optimization:

  • Stability testing across different pH values, salt concentrations, and additives

  • Evaluation of reducing agents to maintain cysteine residues

  • Assessment of detergents if membrane association is suspected

• Functional Validation:

  • Activity assays to confirm proper folding

  • Binding assays with known interaction partners

  • Circular dichroism to assess secondary structure content

Commercially available recombinant human MESDC1 protein (catalog number PRO-1950) may serve as a reference standard for comparison with in-house preparations.

What are the key unanswered questions about MESDC1 that warrant further investigation?

Despite the information available about MESDC1, several key questions remain unanswered and represent promising avenues for future research:

• Precise Molecular Function: While MESDC1 is described as a chaperone for low-density lipoprotein receptors , the specific mechanisms and client repertoire remain to be fully characterized.

• Developmental Roles: The extent to which MESDC1 directly contributes to mesoderm development, as suggested by its name, requires further investigation through developmental model systems.

• Disease Associations: Whether MESDC1 variants or expression changes contribute to human disease phenotypes remains largely unexplored.

• Regulatory Networks: The transcriptional and post-transcriptional mechanisms governing MESDC1 expression across tissues and developmental stages warrant systematic investigation.

• Structural Biology: Three-dimensional structure determination would provide insights into MESDC1's molecular function and potential for targeted modulation.

Researchers addressing these questions would make significant contributions to understanding this protein's biological significance and potential as a therapeutic target or biomarker.

How can integrative approaches advance our understanding of MESDC1 biology?

Advancing MESDC1 research will likely require integrative approaches that combine multiple technologies and perspectives:

• Multi-omics Integration:

  • Correlating genomic variation with transcriptomic, proteomic, and metabolomic changes

  • Identifying regulatory networks through systems biology approaches

  • Applying network medicine concepts to place MESDC1 in broader biological contexts

• Cross-species Comparisons:

  • Leveraging evolutionary conservation to identify critical functional domains

  • Using model organisms to study developmental roles not accessible in human systems

  • Applying comparative genomics to identify conserved regulatory elements

• Computational Biology:

  • Employing machine learning approaches to predict MESDC1 functions and interactions

  • Utilizing structural prediction tools to guide experimental design

  • Developing mathematical models of signaling networks incorporating MESDC1

• Clinical Correlations:

  • Exploring associations between MESDC1 variation/expression and human phenotypes

  • Investigating potential biomarker applications in developmental disorders

  • Assessing therapeutic targeting potential