What is it about?
Neurofibromatosis type 1 (NF1) is a relatively common genetic disorder that causes a range of symptoms in humans. The disorder is caused by mutations in a single gene, but the protein encoded by this gene regulates multiple signaling molecules within cells of the body. Understanding how these complex signaling changes drive the symptoms in the disease is critical for devising new treatments for the disorder. Since there are multiple symptoms and multiple signaling molecules affected, could the different symptoms arise from effects of different signaling molecules? We tested this using fruit flies, which are a great genetic model for NF1. Mutations in the gene that cause NF1 in humans cause several effects in flies, including changing behavior (increasing grooming) and alerting the flies’ metabolism. Yet we found that these two distinct changes were due to effects of different sets of signaling molecules, which act downstream of the genetic mutation. The behavioral effect was due to changes in one set of signaling molecules, while the metabolic alteration was dependent on a distinct set of signaling molecules, with only partial overlap between them. This suggests that treating symptoms in NF1 may require different therapeutic approaches depending on the desired outcome.
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Photo by Karsten Winegeart on Unsplash
Why is it important?
There is currently only one therapeutic treatment for NF1, a class of drugs called MEK inhibitors. These drugs are effective for certain cancers, but it is not used for treatment of non-cancer symptoms, including cognitive or behavioral symptoms. The drugs also produce side effects in some patients. Identifying additional ways to treat NF1 would improve the quality of options available to patients. Understanding how the mutations that cause NF1 produce different symptoms in humans act at the genetic and molecular level, via effects on different signaling molecules, may open novel avenues to treat NF1. The fruit fly provides a powerful platform to test how genes and molecules function in a living organism, in the context of health and disease, and was used here to dissect how the genetic mutations underlying NF1 drive different effects.
Perspectives
This research began with several serendipitous observations, beginning when Dr. Marta Koch noticed that flies with genetic mutations mimicking NF1 in humans groom excessively. A comprehensive study by Drs. Lanikea King, Marta Koch, and colleagues was published in 2016, with a follow-up in 2020. In parallel, Valentina Botero discovered that mutations in this gene increased metabolic rate, publishing her initial finding in 2022. These foundational discoveries laid the groundwork for the present study, examining whether/how the same mutations in one gene could produce different symptoms by affecting different signaling molecules. The research represents the culmination of an exciting period of discovery for the lab. Dr. Valentina Botero led this project, pulling together contributions from a team of talented investigators. We hope that these findings generate provide leads for future identification of new targets to treat neurofibromatosis type 1.
Seth Tomchik
University of Iowa
Read the Original
This page is a summary of: Metabolic and behavioral effects of neurofibromin result from differential recruitment of MAPK and mTOR signaling, PLoS Genetics, March 2026, PLOS,
DOI: 10.1371/journal.pgen.1012061.
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