RASopathies: unraveling mechanisms with animal models

Abstract

RASopathies are developmental disorders caused by germline mutations in the Ras-MAPK pathway, and are characterized by a broad spectrum of functional and morphological abnormalities. The high incidence of these disorders (∼1/1000 births) motivates the development of systematic approaches for their efficient diagnosis and potential treatment. Recent advances in genome sequencing have greatly facilitated the genotyping and discovery of mutations in affected individuals, but establishing the causal relationships between molecules and disease phenotypes is non-trivial and presents both technical and conceptual challenges. Here, we discuss how these challenges could be addressed using genetically modified model organisms that have been instrumental in delineating the Ras-MAPK pathway and its roles during development. Focusing on studies in mice, zebrafish and Drosophila, we provide an up-to-date review of animal models of RASopathies at the molecular and functional level. We also discuss how increasingly sophisticated techniques of genetic engineering can be used to rigorously connect changes in specific components of the Ras-MAPK pathway with observed functional and morphological phenotypes. Establishing these connections is essential for advancing our understanding of RASopathies and for devising rational strategies for their management and treatment.

Cell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders

“…Since then, molecular and cellular studies using mutant mice have provided invaluable insights into the mechanisms and treatments for RASopathies (Jindal et al, 2015;Shilyansky et al, 2010b). Other manifestations in RASopathy, such as heart defects and facial deformities, might be cured by surgical treatments.…”

“…RASopathies share a molecular etiology (i.e., mutations in the RAS pathway) and common clinical features, including heart defects, delayed growth, craniofacial abnormalities, predisposition to developing cancers, and neurocognitive impairments (Bentires-Alj et al, 2006;Rauen, 2013;Zenker, 2011). However, each disease also displays distinct symptoms depending on the specific mutated genes (Jindal, Goyal, Burdine, Rauen, & Shvartsman, 2015). The most intuitive strategy for treating RASopathy would be to target the RAS-MAPK pathway directly.…”

“…Recent studies suggest that RAS-MAPK signaling plays distinct roles in different cell types in mammalian brain depending on its specific interactions with other regulatory proteins such as different GAPs and GEFs (Cui, Costa, Murphy, Elgersma, Zhu, Gutmann et al, 2008;Jindal et al, 2015;Lee, Ehninger, Zhou, Oh, Kang, Kwak et al, 2014). Also in C. elegans, different RasGAP proteins are differentially involved in different types of associative memory (Gyurko, Csermely, Soti, & Stetak, 2015).…”

Modeling RASopathies with Genetically Modified Mouse Models

“…1 ). These mouse models recapitulate most of the key features observed in patients [ 22 ] and are important tools for different type of studies:…”

In vivo severity ranking of Ras pathway mutations associated with developmental disorders

“…Estimated to affect 1/1,000 human births, these abnormalities are characterized by a broad spectrum of phenotypes, including cardiac defects, craniofacial dysmorphisms, and neurocognitive delays (4). Although the origins of these phenotypes are still poorly understood, studies of model organisms show that many of the observed structural and functional defects can indeed be mimicked by targeted introduction of mutations found in RASopathies (5). Hundreds of such mutations have already been identified, and many more are likely to be discovered by the sequencing of affected individuals (6).…”