Genetic activation of ERK2 recapitulates core neurodevelopmental features of Rasopathy syndromes in mice
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 MAP kinases, we engineered mice with a gain-of-function mutation in the terminal MAP kinase gene <i>Mapk1</i>, which encodes ERK2 and is associated with the recently described genetic syndrome <i>MAPK1</i>-related Rasopathy (MRR). <i>Mapk1</i> 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
- Michael T. Williams (ORCID: https://orcid.org/0000-0001-9841-9683)
- Yueh‐Chiang Hu (ORCID: https://orcid.org/0000-0002-7992-0525)
- Carlos E. Prada (ORCID: https://orcid.org/0000-0003-3348-3531)
- A. Volz (ORCID: https://orcid.org/0009-0003-6546-4260)
- Kelly Smallwood (ORCID: https://orcid.org/0000-0001-6411-6510)
- Zoe R Cappel
- Kenneth D. Greis (ORCID: https://orcid.org/0000-0002-5316-3351)
- Diana Nardini (ORCID: https://orcid.org/0000-0002-7121-4343)
- Linde A. Miles (ORCID: https://orcid.org/0000-0003-3578-2842)
- J. Elliott Robinson (ORCID: https://orcid.org/0000-0001-9417-3938)
- Christine A. Berryhill (ORCID: https://orcid.org/0000-0002-4657-2376)
- Tilat A. Rizvi (ORCID: https://orcid.org/0000-0002-0881-9518)
- Ronald R. Waclaw (ORCID: https://orcid.org/0000-0003-4204-4370)
- Lindsey E. Romick‐Rosendale (ORCID: https://orcid.org/0000-0002-7252-1193)
- Nancy Ratner (ORCID: https://orcid.org/0000-0001-5030-9354)
- Evelin M. Cotella (ORCID: https://orcid.org/0000-0002-7909-4008)
- K. Nicole Weaver (ORCID: https://orcid.org/0000-0002-3991-135X)
- Steven P. Angus (ORCID: https://orcid.org/0000-0002-7655-657X)
- Rodrigo F. Salazar (ORCID: https://orcid.org/0000-0003-3530-666X)
- Charles V. Vorhees (ORCID: https://orcid.org/0000-0003-3558-8812)
- Ashley Wooten
- Austen A Fisher
- Kassidy E Grover (ORCID: https://orcid.org/0000-0001-7688-3629)
- Kimaya R Raje
- Mary Claire T Casper
Institutions
- Northwestern University (US)
- Cincinnati Children's Hospital Medical Center (US)
- Lurie Children's Hospital (US)
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Universidad Nacional de Córdoba (AR)
- Lurie Children's Hospital (US)
- Instituto de Investigación Médica Mercedes y Martín Ferreyra (AR)
- University School (US)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
- Indiana University (US)
- University of Cincinnati (US)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-17
- DOI
- https://doi.org/10.64898/2025.12.15.694380
- Primary Topic
- Melanoma and MAPK Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00