GO:1905005 regulation of epithelial to mesenchymal transition involved in endocardial cushion formation: Heart Valve Development, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1905005 describes any process that modulates the frequency, rate or extent of epithelial to mesenchymal transition (EMT) specifically during endocardial cushion formation, a critical step in heart valve and septal development.
• Endocardial cushion formation requires endocardial cells to undergo EMT, delaminate, and invade the underlying myocardium; this process is tightly regulated by signaling pathways including TGFβ, BMP, Wnt, and Notch.
• Key regulators include Tbx20, Bmp2, Tmem100, miR-23b, miR-199a, and YAP, which control the timing and extent of EMT in the atrioventricular canal and outflow tract.
• Dysregulation of this process leads to congenital heart defects such as bicuspid aortic valve, septal defects, and valve malformations.
• Research models include mouse embryos, Syrian hamster, and en face endocardial cushion preparations for planar morphogenesis analysis.
• CRISPR-based knockout, knock-in, and overexpression models enable causal testing of candidate regulators in endocardial cushion EMT.
Description
Epithelial to mesenchymal transition (EMT) is a fundamental developmental process in which polarized epithelial cells lose their cell-cell adhesions and acquire a migratory mesenchymal phenotype. In the embryonic heart, a specialized form of EMT occurs in the endocardium overlying the atrioventricular (AV) canal and outflow tract, leading to the formation of endocardial cushions, the precursors of heart valves and membranous septa. This process is precisely regulated in space and time, and its disruption causes congenital heart defects. GO:1905005, regulation of epithelial to mesenchymal transition involved in endocardial cushion formation, captures the biological processes that modulate the frequency, rate, or extent of this specific EMT event. Understanding these regulatory mechanisms is essential for developmental biologists and clinicians studying heart malformations. The term encompasses signaling pathways, transcription factors, and microRNAs that either promote or inhibit endocardial EMT. Key studies have identified TGFβ, BMP, Wnt, and Notch pathways as central regulators. For example, myocardial Tbx20 regulates early AV canal formation and endocardial EMT via Bmp2. Tmem100 null embryos show impaired endothelial-mesenchymal transformation during AV cushion formation. MicroRNAs such as miR-23b and miR-199a impair EMT during AV endocardial cushion formation. YAP plays a dual role in driving TGFβ-mediated endothelial-to-mesenchymal transition. These findings highlight the complexity of the regulatory network. This article provides a comprehensive overview of GO:1905005, covering its definition, mechanisms, key genes, disease relevance, and research methods, with a focus on CRISPR-based approaches for functional studies.
regulation of epithelial to mesenchymal transition involved in endocardial cushion formation At A Glance
| GO ID | GO:1905005 |
|---|---|
| GO term | regulation of epithelial to mesenchymal transition involved in endocardial cushion formation |
| Ontology | biological_process |
| Synonym | none |
| Major function | Modulates the frequency, rate or extent of EMT during endocardial cushion formation |
| Related process | Epithelial to mesenchymal transition (EMT) |
| Anatomical context | Endocardial cushions of the atrioventricular canal and outflow tract |
| Developmental stage | Embryonic heart development |
| Key signaling pathways | TGFβ, BMP, Wnt, Notch |
What Is GO:1905005?
GO:1905005 is defined as any process that modulates the frequency, rate or extent of epithelial to mesenchymal transition involved in endocardial cushion formation. In simpler terms, it includes all molecular and cellular events that control how often, how fast, or how extensively endocardial cells transform into mesenchymal cells during the formation of the heart's cushion tissues. This regulation ensures proper heart valve and septal development, and its perturbation can lead to congenital heart defects.
Why Is regulation of epithelial to mesenchymal transition involved in endocardial cushion formation Important in Cell Biology?
GO:1905005 is critical because endocardial cushion formation is a prerequisite for proper heart valve and septal development. Disruption of this regulatory process leads to congenital heart defects, the most common birth defects in humans. Understanding the molecular players that modulate EMT in endocardial cushions provides insights into both normal cardiogenesis and disease mechanisms, and offers potential targets for therapeutic intervention.
• Endocardial cushion EMT is essential for heart valve and septal formation.
• Dysregulation causes congenital heart defects such as bicuspid aortic valve and septal defects.
• TGFβ, BMP, Wnt, and Notch signaling pathways converge to regulate this process.
• Transcription factors like Tbx20 and Tmem100 are key regulators.
• MicroRNAs such as miR-23b and miR-199a modulate EMT during cushion formation.
• YAP integrates mechanical and biochemical signals to drive endothelial-to-mesenchymal transition.
• Animal models including mouse and Syrian hamster are used to study this process.
• CRISPR gene editing enables precise functional dissection of regulatory genes.
• Understanding this process aids in developing diagnostics and therapies for heart valve diseases.
• The term is a focus of developmental biology and regenerative medicine research.
What Happens During regulation of epithelial to mesenchymal transition involved in endocardial cushion formation?
Initiation of EMT in the endocardium
In simple terms: Endocardial cells receive signals to start transforming.
In the developing heart, endocardial cells lining the AV canal and outflow tract receive inductive signals from the adjacent myocardium, including BMP2 and TGFβ. These signals trigger the endocardial cells to lose their epithelial characteristics and initiate EMT. Myocardial Tbx20 regulates early AV canal formation and endocardial EMT via Bmp2.
Transcriptional and post-transcriptional regulation
In simple terms: Genes and microRNAs control the EMT program.
Transcription factors such as Snail, Slug, and Twist are activated downstream of TGFβ and BMP signaling to repress epithelial genes and activate mesenchymal genes. MicroRNAs such as miR-23b and miR-199a impair EMT during AV endocardial cushion formation, acting as negative regulators. Tmem100 modulates endothelial-mesenchymal transformation, as its loss impairs cushion formation.
Cellular changes and delamination
In simple terms: Cells change shape, detach, and migrate into the cushion matrix.
Endocardial cells undergo changes in cell-cell adhesion, lose apical-basal polarity, and delaminate from the endocardial monolayer. They invade the underlying extracellular matrix-rich cushion tissue. This process is driven by cytoskeletal rearrangements and matrix metalloproteinases. YAP plays a dual role in driving TGFβ-mediated endothelial-to-mesenchymal transition, influencing both initiation and progression.
Signaling pathways modulating EMT
In simple terms: Multiple signals fine-tune the EMT process.
The canonical Wnt signaling pathway plays a role in heart valve development, modulating EMT and cushion formation. TGFβ signaling is central, with YAP acting as a mediator. BMP signaling, particularly BMP2 from the myocardium, is essential. Notch signaling also contributes to endocardial EMT regulation. These pathways form a complex network that ensures proper timing and extent of EMT.
Resolution and cushion maturation
In simple terms: The newly formed mesenchymal cells organize into cushion tissue.
After EMT, the mesenchymal cells proliferate and contribute to the endocardial cushions, which later remodel into heart valves and septa. Regulation of EMT must be tightly controlled; excessive or insufficient EMT leads to malformations. The Syrian hamster model has been used to show that endocardial-to-mesenchymal transition underlies cardiac outflow tract septation and bicuspid aortic valve formation.
Key Genes Involved in GO:1905005 regulation of epithelial to mesenchymal transition involved in endocardial cushion formation
The following genes and proteins are key regulators of epithelial to mesenchymal transition involved in endocardial cushion formation, as supported by published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| Tbx20 | Transcription factor regulating early AV canal formation and endocardial EMT via Bmp2 | Knockout studies show impaired EMT and cushion defects |
| Bmp2 | Secreted growth factor from myocardium that induces EMT | Conditional knockout models demonstrate its necessity for cushion formation |
| Tmem100 | Transmembrane protein modulating endothelial-mesenchymal transformation | Null embryos exhibit impaired AV cushion formation |
| YAP | Transcriptional co-activator driving TGFβ-mediated endothelial-to-mesenchymal transition | Dual role in EMT; knockout/overexpression models |
| miR-23b | MicroRNA that impairs EMT during AV endocardial cushion formation | Overexpression inhibits EMT; potential therapeutic target |
| miR-199a | MicroRNA that impairs EMT during AV endocardial cushion formation | Overexpression inhibits EMT; potential therapeutic target |
| TGFβ | Signaling ligand that induces EMT | Central regulator; modulation affects cushion formation |
| Wnt | Signaling pathway involved in heart valve development | Canonical Wnt signaling modulates EMT |
| Notch | Signaling pathway contributing to endocardial EMT | Interplays with TGFβ and BMP |
| Snail | Transcriptional repressor of E-cadherin, promotes EMT | Downstream effector of TGFβ/BMP |
| Slug | Transcriptional repressor of E-cadherin, promotes EMT | Downstream effector of TGFβ/BMP |
| Twist | Transcription factor promoting mesenchymal phenotype | Downstream effector of TGFβ/BMP |
| VEGF | Angiogenic factor that can modulate EMT | Potential regulator in cushion formation |
| NFATc1 | Transcription factor involved in valve development | Regulates EMT and cushion remodeling |
| ErbB | Receptor tyrosine kinase signaling | Modulates EMT in cushion |
| Periostin | Extracellular matrix protein | Supports cushion matrix and EMT |
| Hyaluronan | Extracellular matrix component | Essential for cushion expansion and EMT |
How Is regulation of epithelial to mesenchymal transition involved in endocardial cushion formation Regulated?
The regulation of EMT in endocardial cushion formation is orchestrated by a complex interplay of signaling pathways and transcription factors. TGFβ signaling is a master regulator, activating downstream effectors such as Smads and YAP. BMP2 from the myocardium induces EMT through Tbx20-dependent mechanisms. Wnt/β-catenin signaling modulates EMT and valve development. Notch signaling interacts with TGFβ and BMP to fine-tune EMT. MicroRNAs such as miR-23b and miR-199a provide post-transcriptional inhibition. Tmem100 modulates endothelial-mesenchymal transformation, and its loss impairs cushion formation. These regulatory layers ensure precise spatiotemporal control of EMT.
regulation of epithelial to mesenchymal transition involved in endocardial cushion formation and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| Tmem100 | Impaired AV cushion formation | Tmem100 knockout mouse |
| Tbx20 | AV canal and EMT defects | Myocardial-specific Tbx20 knockout |
| miR-23b | Inhibition of EMT, valve malformations | Overexpression in endocardial cells |
| YAP | Dysregulated EMT, valve disease | Conditional knockout/overexpression |
| Bmp2 | Cushion and septal defects | Myocardial Bmp2 knockout |
Congenital heart defects
Disruption of endocardial cushion EMT regulation leads to congenital heart defects, including bicuspid aortic valve, ventricular septal defects, and valve stenosis. The Syrian hamster model has demonstrated that endocardial-to-mesenchymal transition underlies cardiac outflow tract septation and bicuspid aortic valve formation. Tmem100 null embryos show impaired AV cushion formation, linking this gene to developmental heart defects.
Valve malformations
Abnormal EMT during cushion formation can result in thickened or malformed valves, such as in aortic valve stenosis. MicroRNAs miR-23b and miR-199a impair EMT, and their dysregulation may contribute to valve disease. Wnt signaling abnormalities are also associated with valve malformations.
Septal defects
Proper endocardial cushion formation is required for membranous septal closure. Impaired EMT can lead to atrial or ventricular septal defects. Tbx20 and Bmp2 mutations are linked to septal defects in animal models.
From regulation of epithelial to mesenchymal transition involved in endocardial cushion formation-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X regulate endocardial EMT? | Knockout mouse (conditional or global) |
| What is the effect of a point mutation in gene X on EMT? | Point-mutation knock-in mouse |
| How does overexpression of gene X affect cushion formation? | Transgenic overexpression mouse |
| Where and when is gene X expressed during EMT? | Tagged knock-in reporter mouse |
| What are the downstream targets of gene X? | RNA-seq and ChIP-seq in mutant embryos |
| Can we rescue the phenotype by re-expressing gene X? | Knock-in rescue model |
How to Study the regulation of epithelial to mesenchymal transition involved in endocardial cushion formation Process
| Method | What It Measures | Typical Application |
|---|---|---|
| En face endocardial cushion preparation | Planar morphogenesis and EMT | Visualizing cell shape changes and delamination |
| RNA-seq | Transcriptome changes | Identifying EMT regulators |
| miRNA profiling | MicroRNA expression | Discovering inhibitory microRNAs |
| ChIP-seq | Transcription factor binding | Mapping Tbx20, YAP targets |
| Immunofluorescence | Protein localization | Detecting EMT markers (e.g., Snail, E-cadherin) |
| Lineage tracing | Cell fate | Tracking endocardial-derived mesenchymal cells |
| Western blot | Protein expression and signaling | Assessing TGFβ/BMP pathway activation |
| Luciferase reporter | Transcriptional activity | Measuring Wnt/β-catenin signaling |
Lineage tracing and en face imaging
En face endocardial cushion preparation allows planar morphogenesis analysis in mouse embryos, enabling visualization of EMT and cell migration. Lineage tracing using Tie2-Cre or Nfatc1-Cre labels endocardial cells and their mesenchymal descendants.
Transcriptomics and microRNA profiling
RNA-seq of microdissected AV cushions or sorted endocardial cells can identify differentially expressed genes and microRNAs during EMT. miR-23b and miR-199a were identified as regulators through such approaches.
Protein interaction and signaling assays
Co-immunoprecipitation, Western blotting, and luciferase reporter assays can dissect TGFβ, BMP, and Wnt signaling activity. YAP-TGFβ crosstalk was elucidated using such methods.
Genetic manipulation in animal models
Conditional knockout, knock-in, and overexpression in mice are standard for testing gene function in endocardial EMT. The Syrian hamster model provides an alternative for outflow tract and bicuspid aortic valve studies.
How CRISPR Can Be Used to Study GO:1905005 regulation of epithelial to mesenchymal transition involved in endocardial cushion formation
Knockout
CRISPR knockout of candidate genes in mouse embryos or cell lines can test their necessity for endocardial EMT. For example, Tmem100 knockout recapitulates impaired cushion formation. Conditional knockout using Cre-loxP allows tissue-specific deletion.
Point Mutation
Introducing specific point mutations via CRISPR base editing or HDR can model human variants associated with congenital heart defects. This helps distinguish pathogenic from benign variants in genes like Tbx20 or Bmp2.
Knock-in
Knock-in of reporter tags (e.g., GFP, lacZ) or human disease alleles enables visualization and functional studies. Tagged knock-in of Tmem100 or YAP allows tracking of protein localization and dynamics.
Overexpression
CRISPR activation (CRISPRa) or transgenic overexpression can test sufficiency of a gene to drive EMT. Overexpression of miR-23b or miR-199a impairs EMT, demonstrating their inhibitory role.
How EDITGENE Supports regulation of epithelial to mesenchymal transition involved in endocardial cushion formation Research
Researchers studying regulation of epithelial to mesenchymal transition involved in endocardial cushion formation-related genes often need to determine whether a candidate gene is causally involved in the process or merely correlated. EDITGENE provides comprehensive CRISPR-based services to enable such functional studies.
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Frequently Asked Questions About regulation of epithelial to mesenchymal transition involved in endocardial cushion formation
What is GO:1905005?
GO:1905005 is a Gene Ontology biological process term defined as any process that modulates the frequency, rate or extent of epithelial to mesenchymal transition involved in endocardial cushion formation.
What genes are involved in regulation of epithelial to mesenchymal transition involved in endocardial cushion formation?
Key genes include Tbx20, Bmp2, Tmem100, YAP, miR-23b, miR-199a, and components of TGFβ, Wnt, and Notch signaling pathways.
Why is endocardial cushion EMT important?
It is essential for heart valve and septal development; dysregulation causes congenital heart defects.
What signaling pathways regulate endocardial EMT?
TGFβ, BMP, Wnt, and Notch pathways are major regulators.
What animal models are used to study endocardial cushion EMT?
Mouse embryos, Syrian hamster, and en face endocardial cushion preparations are commonly used.
How do microRNAs affect endocardial EMT?
miR-23b and miR-199a impair EMT during AV endocardial cushion formation.
What is the role of Tmem100 in endocardial cushion formation?
Tmem100 modulates endothelial-mesenchymal transformation; its loss impairs AV cushion formation.
How does YAP regulate endocardial EMT?
YAP plays a dual role in driving TGFβ-mediated endothelial-to-mesenchymal transition.
What diseases are associated with defects in endocardial cushion EMT?
Congenital heart defects including bicuspid aortic valve, septal defects, and valve malformations.
How can CRISPR be used to study endocardial EMT?
CRISPR knockout, knock-in, point mutation, and overexpression models enable functional testing of candidate genes in endocardial EMT.
Conclusion
GO:1905005 encompasses the regulatory mechanisms that control epithelial to mesenchymal transition during endocardial cushion formation, a process critical for heart valve and septal development. Dysregulation of this process leads to congenital heart defects, making it a key area of developmental and clinical research. Advances in CRISPR gene editing and animal models continue to unravel the complex signaling networks and gene regulatory mechanisms involved. Understanding these pathways offers potential for diagnostic and therapeutic strategies for heart valve diseases.
References
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- 2. Savorani C et al.. 2021. A dual role of YAP in driving TGFβ-mediated endothelial-to-mesenchymal transition.. J Cell Sci 134(15) PMID: 34338295
- 3. Mizuta K et al.. 2015. Impairment of endothelial-mesenchymal transformation during atrioventricular cushion formation in Tmem100 null embryos.. Dev Dyn 244(1):31-42 PMID: 25318679
- 4. Bonet F et al.. 2015. MiR-23b and miR-199a impair epithelial-to-mesenchymal transition during atrioventricular endocardial cushion formation.. Dev Dyn 244(10):1259-75 PMID: 26198058
- 5. Gonzalez-Costa T et al.. 2022. En Face Endocardial Cushion Preparation for Planar Morphogenesis Analysis in Mouse Embryos.. J Vis Exp PMID: 35969077
- 6. Person AD et al.. 2005. Cell biology of cardiac cushion development.. Int Rev Cytol 243:287-335 PMID: 15797462
- 7. Zhang RR et al.. 2015. [Role of the canonical Wnt signaling pathway in heart valve development].. Zhongguo Dang Dai Er Ke Za Zhi 17(7):757-62 PMID: 26182289
- 8. Cai X et al.. 2011. Myocardial Tbx20 regulates early atrioventricular canal formation and endocardial epithelial-mesenchymal transition via Bmp2.. Dev Biol 360(2):381-90 PMID: 21983003
