Genetic activation of ERK2 recapitulates core neurodevelopmental features of Rasopathy syndromes in mice

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Rasopathies are a group of rare neurodevelopmental disorders caused by germline pathogenic variants activating the Ras/mitogen-activated protein kinase (MAPK) pathway.
• Causative mutations may affect multiple Ras-dependent pathways beyond MAPK signaling, complicating the understanding of specific disease sequelae.

Purpose of the Study:

• To investigate the role of downstream MAPK hyperactivation in Rasopathy pathogenesis.
• To model the recently described MAPK1-related Rasopathy (MRR) using a gain-of-function mutation in the Mapk1 gene.

Main Methods:

• Engineered mice with a gain-of-function mutation in the Mapk1 gene, which encodes ERK2.
• Phenotypic analysis of Mapk1 mutant mice to assess recapitulation of human MRR and other Rasopathy features.

Main Results:

• Mapk1 mutant mice successfully modeled key aspects of human MRR, including small stature, facial dysmorphism, and cognitive impairment.
• These mice also recapitulated phenotypes seen in upstream Ras-activated Rasopathies like neurofibromatosis type 1 (NF1), including oligodendrocyte lineage defects, astrogliosis, memory deficits, and sensory hypersensitivity.

Conclusions:

• Downstream MAPK signaling, specifically via ERK2, plays a critical role in the pathophysiology of neurocognitive symptoms in Rasopathy syndromes.
• The Mapk1 mutant mouse model is valuable for studying MRR and understanding the broader impact of MAPK pathway dysregulation in Rasopathies.