ERK Inhibition Rescues Defects in Fate Specification of Nf1-Deficient Neural Progenitors and Brain Abnormalities
Open accessAbstract
Germline mutations in the RAS/ERK signaling pathway underlie several related developmental disorders collectively termed neuro-cardio-facial-cutaneous (NCFC) syndromes. NCFC patients manifest varying degrees of cognitive impairment, but the developmental basis of their brain abnormalities remains largely unknown. Neurofibromatosis type 1 (NF1), an NCFC syndrome, is caused by loss-of-function heterozygous mutations in the NF1 gene, which encodes neurofibromin, a RAS GTPase-activating protein. Here, we show that biallelic Nf1 inactivation promotes Erk-dependent, ectopic Olig2 expression specifically in transit-amplifying progenitors, leading to increased gliogenesis at the expense of neurogenesis in neonatal and adult subventricular zone (SVZ). Nf1-deficient brains exhibit enlarged corpus callosum, a structural defect linked to severe learning deficits in NF1 patients. Strikingly, these NF1-associated developmental defects are rescued by transient treatment with an MEK/ERK inhibitor during neonatal stages. This study reveals a critical role for Nf1 in maintaining postnatal SVZ-derived neurogenesis and identifies a potential therapeutic window for treating NF1-associated brain abnormalities.
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Activity of β-catenin enhances premature differentiation of neurons, while activity of RAS/ERK reduces neurogenesis of IPCs and increases astrogenesis.
“Activity of β-catenin (downstream of PI3K/AKT and WNT, Fig. 6) enhances premature differentiation of neurons [88], while activity of RAS/ERK reduces neurogenesis of IPCs and increases astrogenesis [90].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [90]
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ERK signalling: A master regulator of cell behaviour, life and fate
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- Authors
- Wang, Y., Kim, E., Wang, X., Novitch, B. G., Yoshikawa, K., Chang, L.-S., & Zhu, Y.
- Affiliations
- University of Michigan (US)
- University of California, Los Angeles (US)
- Institute for Protein Research, The University of Osaka (JP)
- Nationwide Children's Hospital (US)
- Corresponding author
- Zhu, Yuan
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 150
- Issue
- 4
- Pages
- 816-830
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3427010
- OpenAlex
- W2087705653
- Cited by
- 151
- References
- 52
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 13 · 2023: 8 · 2022: 8 · 2021: 15 · 2020: 8 · 2019: 13 · 2018: 13 · 2017: 11 · 2016: 10 · 2015: 16 · 2014: 10 · 2013: 10 · 2012: 4
- FWCI
- 4.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1R01 NS053900)
- U.S. Department of Defense (W81XWH-11-1-0251)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- neurofibromatosis type 1, Ras/ERK signaling, MEK/ERK inhibitor, neural progenitor cells, subventricular zone, gliogenesis, neurogenesis, Olig2, learning deficits, neurofibromin
- MeSH terms
- Oligodendrocyte Transcription Factor 2, Animals, Brain, Corpus Callosum, Humans, Nerve Tissue Proteins, Neurofibromatosis 1, Neuroglia, Mice, Knockout, MAP Kinase Signaling System, Neurofibromin 1, Mice, Basic Helix-Loop-Helix Proteins, Neural Stem Cells
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