Genetic activation of ERK2 recapitulates core neurodevelopmental features of Rasopathy syndromes in mice
Year: 2026
Type: article
Abstract: Germline pathogenic variants that activate the Ras/mitogen-activated protein kinase (MAPK) pathway cause neurodevelopmental disorders called Rasopathies. Because many affected proteins directly regulate Ras, causative mutations may alter other Ras-dependent pathways in addition to MAPK signaling. To better understand which Rasopathy sequelae result from hyperactivation of downstream MAPKs, we engineered mice with a gain-of-function mutation in the terminal MAPK gene Mapk1, which encodes ERK2 and is associated with the recently described genetic syndrome MAPK1-related Rasopathy (MRR). Mapk1 mutant mice successfully modeled key aspects of the human MRR phenotype, including small stature, facial dysmorphism, and impaired cognitive function. Importantly, they recapitulated phenotypes identified in Rasopathy models with upstream Ras activation, such as neurofibromatosis type 1 (NF1): oligodendrocyte lineage defects, reactive astrogliosis, memory deficits, and hypersensitivity to sensory stimuli. These findings emphasize the importance of downstream MAPK signaling in the pathophysiology of neurocognitive symptoms observed in Rasopathy syndromes.
Authors: Kassidy E. Grover, Zoe R. Cappel, Avery M. Volz, Evelin M. Cotella, Kelly Smallwood, Christine A. Berryhill, Kimaya R. Raje, Austen A. Fisher, Mary Claire T. Casper, Diana Nardini, Tilat A. Rizvi, Rosa M. Salazar, Ashley Wooten, Michael T. Williams, Charles V. Vorhees, Lindsey E. Romick, Kenneth D. Greis, Yueh-Chiang Hu, Linde A. Miles, Steven P. Angus, Nancy Ratner, Carlos E. Prada, K. Nicole Weaver, Ronald R. Waclaw, J. Elliott Robinson
Institutions: Cincinnati Children's Hospital Medical Center, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Córdoba, Instituto de Investigación Médica Mercedes y Martín Ferreyra, Indiana University School of Medicine, University of Cincinnati, University of Cincinnati Medical Center, Northwestern University, Lurie Children's Hospital
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,300
OpenAlex ID: W4417448444