Logo image
Back
Metabolic and behavioral effects of neurofibromin result from differential recruitment of MAPK and mTOR signaling
Preprint   Open access

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

Valentina Botero, Jenifer Barrios, Anneke Knauss, Ethan Rosendahl, Kenneth J Colodner and Seth M Tomchik
bioRxiv
Cold Spring Harbor Laboratory
07/30/2025
DOI: 10.1101/2025.07.25.666841
PMCID: PMC12324403
PMID: 40766628
url
https://doi.org/10.1101/2025.07.25.666841View
Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Neurofibromatosis type 1 results from mutations in the Neurofibromin 1 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 of MEK/ERK and Akt/mTOR/S6K/4E-BP signaling. At the systemic level, neurofibromin dysregulated metabolism via molecular effects of Nf1 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 down-stream of Ras, which differentially affect metabolic and behavioral neurofibromatosis type 1 phenotypes.Neurofibromatosis type 1 results from mutations in the Neurofibromin 1 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 of MEK/ERK and Akt/mTOR/S6K/4E-BP signaling. At the systemic level, neurofibromin dysregulated metabolism via molecular effects of Nf1 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 down-stream of Ras, which differentially affect metabolic and behavioral neurofibromatosis type 1 phenotypes.

Details

Metrics

36 Record Views
Logo image