Disrupted ERK Signaling during Cortical Development Leads to Abnormal Progenitor Proliferation, Neuronal and Network Excitability and Behavior, Modeling Human Neuro-Cardio-Facial-Cutaneous and Related Syndromes
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Genetic disorders arising from copy number variations in the ERK (extracellular signal-regulated kinase) MAP (mitogen-activated protein) kinases or mutations in their upstream regulators that result in neuro-cardio-facial-cutaneous syndromes are associated with developmental abnormalities, cognitive deficits, and autism. We developed murine models of these disorders by deleting the ERKs at the beginning of neurogenesis and report disrupted cortical progenitor generation and proliferation, which leads to altered cytoarchitecture of the postnatal brain in a gene-dose-dependent manner. We show that these changes are due to ERK-dependent dysregulation of cyclin D1 and p27(Kip1), resulting in cell cycle elongation, favoring neurogenic over self-renewing divisions. The precocious neurogenesis causes premature progenitor pool depletion, altering the number and distribution of pyramidal neurons. Importantly, loss of ERK2 alters the intrinsic excitability of cortical neurons and contributes to perturbations in global network activity. These changes are associated with elevated anxiety and impaired working and hippocampal-dependent memory in these mice. This study provides a novel mechanistic insight into the basis of cortical malformation which may provide a potential link to cognitive deficits in individuals with altered ERK activity.
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Genetic abrogation of Erk2 causes significant developmental changes.
“Consistent with this hypothesis, previous reports have indicated significant developmental changes by genetic abrogation of Erk2222324, but not in Erk1 KO mice25.”
From Transient blockade of ERK phosphorylation in the critical period causes autistic phenotypes as an adult in mice (2015) · cites this paper as [24]
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- Authors
- Pucilowska, J., Puzerey, P. A., Karlo, J. C., Galan, R. F., & Landreth, G. E.
- Affiliations
- Case Western Reserve University (US)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-06-20
- Volume
- 32
- Issue
- 25
- Pages
- 8663-8677
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6620980
- OpenAlex
- W2165890492
- Cited by
- 99
- References
- 59
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 6 · 2022: 8 · 2021: 8 · 2020: 3 · 2019: 7 · 2018: 8 · 2017: 10 · 2016: 4 · 2015: 12 · 2014: 11 · 2013: 6 · 2012: 2
- FWCI
- 3.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mt. Sinai Health Care Foundation
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Keywords
- ERK signaling, copy number variation, cortical development, cyclin D1, p27, neuronal excitability, neuronal network activity, anxiety, working memory, hippocampal-dependent memory, malformations of cortical development, autism spectrum disorder, mitogen-activated protein kinase, mouse model
- MeSH terms
- Animals, Antimetabolites, Anxiety, Behavior, Animal, Bromodeoxyuridine, Cerebral Cortex, Cognition Disorders, Conditioning, Operant, Image Processing, Computer-Assisted, Immunohistochemistry, Male, Mice, Inbred C57BL, Nerve Net, Nervous System Diseases, Neurons, Stem Cells, Blotting, Western, Signal Transduction, Mice, Knockout, Patch-Clamp Techniques, Maze Learning, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Mice
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