Metabolic and behavioral effects of neurofibromin result from differential recruitment of MAPK and mTOR signaling

Valentina Botero; Jenifer Barrios; Anneke Knauss; Greta Dahlen; Ethan Rosendahl; Kenneth J Colodner; Seth M Tomchik

doi:10.1371/journal.pgen.1012061

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Metabolic and behavioral effects of neurofibromin result from differential recruitment of MAPK and mTOR signaling

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Peer reviewed

Metabolic and behavioral effects of neurofibromin result from differential recruitment of MAPK and mTOR signaling

Valentina Botero, Jenifer Barrios, Anneke Knauss, Greta Dahlen, Ethan Rosendahl, Kenneth J Colodner and Seth M Tomchik

PLoS genetics, Vol.22(3), e1012061

03/05/2026

DOI: 10.1371/journal.pgen.1012061

PMCID: PMC12974851

PMID: 41785270

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Abstract

Neurofibromatosis type 1 results from mutations in the NF1 gene and its encoded neurofibromin protein. This condition produces multiple symptoms, including tumors, behavioral alterations, and metabolic changes. Molecularly, neurofibromin mutations affect Ras activity, influencing multiple downstream signaling pathways, including MAPK (Raf/MEK/ERK) and PI3K/Akt/mTOR signaling. This pleiotropy raises the question of which pathways could be targeted to treat the disease symptoms, and whether different phenotypes driven by neurofibromin mutations exhibit similar or diverging dependence on the signaling pathways downstream of Ras. To test this, we examined metabolic and behavioral alterations in the genetically tractable Drosophila neurofibromatosis type 1 model. In vivo genetic analysis revealed that behavioral effects of neurofibromin were mediated by MEK signaling, with no necessity for Akt. In contrast, metabolic effects of neurofibromin were mediated by coordinated actions MEK/ERK and Akt/mTOR/S6K/4E-BP signaling. At the systemic level, loss of neurofibromin dysregulated metabolism via molecular effects in interneurons and muscle. These changes were accompanied by altered muscle mitochondria morphology, with no concomitant changes in neuronal ultrastructure or neuronal mitochondria. Overall, this suggests that neurofibromin mutations affect multiple signaling cascades downstream of Ras, which differentially affect metabolic and behavioral neurofibromatosis type 1 phenotypes.

Details

Title: Subtitle: Metabolic and behavioral effects of neurofibromin result from differential recruitment of MAPK and mTOR signaling
Creators: Valentina Botero - University of Iowa
Jenifer Barrios - University of Iowa
Anneke Knauss - University of Iowa
Greta Dahlen - University of Iowa
Ethan Rosendahl - University of Iowa
Kenneth J Colodner - Mount Holyoke College
Seth M Tomchik - University of Iowa
Resource Type: Journal article
Publication Details: PLoS genetics, Vol.22(3), e1012061
DOI: 10.1371/journal.pgen.1012061
PMID: 41785270
PMCID: PMC12974851
NLM abbreviation: PLoS Genet
ISSN: 1553-7404
eISSN: 1553-7404
Publisher: PLOS
Grant note: National Institute of Neurological Disorders and Stroke: R01NS114403 U.S. Department of Defense: NF230039 Roy J. Carver Charitable Trust: N/A
This research was supported by the National Institutes of Health R01 NS114403 to SMT, R01 NS124716 to SMT, R01 NS126361 to SMT, R01 NS097237 to SMT, R21 NS124198 to SMT, Department of Defense NF230039 to SMT, and an award from the Roy J. Carver Charitable Trust to SMT. VB, JB, AK, GD, ER, and SMT received salary support from the National Institutes of Health and SMT received salary support from the Department of Defense. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Language: English
Date published: 03/05/2026
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neuroscience and Pharmacology
Record Identifier: 9985141959102771

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