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Swimming toward solutions: Using fish and frogs as models for understanding RASopathies
Victoria L Patterson1, Rebecca D Burdine1
1Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.
Abstract:
The RAS signaling pathway regulates cell growth, survival, and differentiation, and its inappropriate activation is associated with disease in humans. The RASopathies, a set of developmental syndromes, arise when the pathway is overactive during development. Patients share a core set of symptoms, including congenital heart disease, craniofacial anomalies, and neurocognitive delay. Due to the conserved nature of the pathway, animal models are highly informative for understanding disease etiology, and zebrafish and Xenopus are emerging as advantageous model systems. Here we discuss these aquatic models of RASopathies, which recapitulate many of the core symptoms observed in patients. Craniofacial structures become dysmorphic upon expression of disease-associated mutations, resulting in wider heads. Heart defects manifest as delays in cardiac development and changes in heart size, and behavioral deficits are beginning to be explored. Furthermore, early convergence and extension defects cause elongation of developing embryos: this phenotype can be quantitatively assayed as a readout of mutation strength, raising interesting questions regarding the relationship between pathway activation and disease. Additionally, the observation that RAS signaling may be simultaneously hyperactive and attenuated suggests that downregulation of signaling may also contribute to etiology. We propose that models should be characterized using a standardized approach to allow easier comparison between models, and a better understanding of the interplay between mutation and disease presentation.
Insights
Aquatic models like zebrafish and Xenopus are valuable for studying RASopathies, developmental syndromes caused by RAS pathway overactivation. These models effectively mimic human symptoms, aiding in understanding disease mechanisms and potential treatments.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- The RAS signaling pathway is crucial for cell growth, survival, and differentiation.
- Dysregulation of the RAS pathway leads to RASopathies, a group of human developmental syndromes.
- Key patient symptoms include congenital heart disease, craniofacial anomalies, and neurocognitive delay.
Purpose of the Study:
- To discuss the utility of aquatic model systems (zebrafish and Xenopus) for studying RASopathies.
- To highlight how these models recapitulate core symptoms observed in human patients.
- To explore the relationship between RAS pathway activation strength and disease presentation.
Main Methods:
- Expression of disease-associated RAS mutations in zebrafish and Xenopus embryos.
- Observation and quantitative assaying of developmental phenotypes, including craniofacial and cardiac defects.
- Analysis of embryonic elongation as a readout of mutation strength.
Main Results:
- Aquatic models display dysmorphic craniofacial structures (e.g., wider heads) and cardiac development delays.
- Embryonic elongation due to convergence and extension defects serves as a quantifiable measure of mutation impact.
- Evidence suggests both hyperactivity and attenuation of RAS signaling may contribute to disease etiology.
Conclusions:
- Zebrafish and Xenopus are advantageous model systems for investigating RASopathies due to conserved pathways.
- These models offer insights into the complex interplay between RAS mutation strength and disease manifestation.
- A standardized approach for characterizing these models is proposed to facilitate comparative studies and enhance understanding.
