The impact of RASopathy-associated mutations on CNS development in mice and humans

Abstract

The RAS signaling pathway is involved in the regulation of developmental processes, including cell growth, proliferation, and differentiation, in the central nervous system (CNS). Germline mutations in the RAS signaling pathway genes are associated with a group of neurodevelopmental disorders, collectively called RASopathy, which includes neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, and Costello syndrome. Most mutations associated with RASopathies increase the activity of the RAS-ERK signaling pathway, and therefore, most individuals with RASopathies share common phenotypes, such as a short stature, heart defects, facial abnormalities, and cognitive impairments, which are often accompanied by abnormal CNS development. Recent studies using mouse models of RASopathies demonstrated that particular mutations associated with each disorder disrupt CNS development in a mutation-specific manner. Here, we reviewed the recent literatures that investigated the developmental role of RASopathy-associated mutations using mutant mice, which provided insights into the specific contribution of RAS-ERK signaling molecules to CNS development and the subsequent impact on cognitive function in adult mice.

Neuron type-specific expression of a mutant KRAS impairs hippocampal-dependent learning and memory

“…www.nature.com/scientificreports/ Cell type specific roles of RAS signalling in learning and memory. It has been shown that the RAS proteins are critically involved in learning and memory and synaptic plasticity 16,27 . Hyperactivation as well as hypoactivation of RAS-ERK signalling impairs learning and memory and synaptic plasticity 16,[27][28][29] .…”

“…As previously shown, since RAS signalling networks are different between excitatory and inhibitory neurons, we speculate that KRAS-ERK signalling pathway is not coupled to pro-apoptotic signalling in inhibitory neurons. Previous studies have shown that mutations in genes involved in the RAS signalling pathway can alter the composition of cell types in both the developing and adult brain 16,39,40 . Changes in the ratio of excitatory and inhibitory neurons can subsequently distort the excitation-inhibition balance, which is critical for normal cognitive functions, including learning and memory 41,42 .…”

“…Changes in the ratio of excitatory and inhibitory neurons can subsequently distort the excitation-inhibition balance, which is critical for normal cognitive functions, including learning and memory 41,42 . Excitatory neuron-specific cell death in adults, which contribute to behavioural deficits, might have been overlooked and may also contribute to the increased inhibition to excitation ratio which has been reported in other RASopathy models 16,18,30,32 . However, we cannot completely exclude the possibility that the disrupted cellular organization in CA1, including the enlarged intercellular space in CA regions, might also have affected the synaptic connectivity in the hippocampus, thereby contributing to behavioural deficits.…”

Core clinical symptoms and heterogeneous manifestations of NS / LAH: three case reports and review of the literature

“…Rasopathies is a type of syndrome with phenotypic overlap. Mutations in the relevant functional genes and downstream signaling genes in this pathway lead to RAS-related diseases (1). NS(Noonan syndromes)are the most common Rasopathy disease.…”

Endosomal trafficking defects alter neural progenitor proliferation and cause microcephaly

“…On the opposite end of the spectrum, megalencephaly (MEG) is a neuronal disorder characterized by brain overgrowth (3 SD over the mean) 18 . The causes of megalencephaly are diverse, but activating mutations in the Pi3K-AKT-mTOR and the Ras-MAPK pathways have been identified as important underlying events [19][20][21] . Mouse and cerebral organoid models for these activated pathways demonstrated increased proliferation of radial glial cells leading to tissue overgrowth [22][23][24] .…”