A haploinsufficiency restoration strategy corrects neurobehavioral deficits in Nf1+/– mice
Su Jung Park, … , Steven P. Angus, D. Wade Clapp
Su Jung Park, … , Steven P. Angus, D. Wade Clapp
Published July 1, 2025
Citation Information: J Clin Invest. 2025;135(13):e188932. https://doi.org/10.1172/JCI188932.
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Research Article Genetics Neuroscience

A haploinsufficiency restoration strategy corrects neurobehavioral deficits in Nf1+/– mice

Abstract

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations of the NF1 tumor suppressor gene resulting in the loss of function of neurofibromin, a GTPase-activating protein (GAP) for Ras. While the malignant manifestations of NF1 are associated with loss of heterozygosity of the residual WT allele, the nonmalignant neurodevelopmental sequelae, including autism spectrum disorder (ASD) and/or attention deficit hyperactivity disorder (ADHD) are prevalent morbidities that occur in the setting of neurofibromin haploinsufficiency. We reasoned that augmenting endogenous levels of WT neurofibromin could serve as a potential therapeutic strategy to correct the neurodevelopmental manifestations of NF1. Here, we used a combination of genetic screening and genetically engineered murine models to identify a role for the F-box protein FBXW11 as a regulator of neurofibromin degradation. Disruption of Fbxw11, through germline mutation or targeted genetic manipulation in the nucleus accumbens, increased neurofibromin levels, suppressed Ras-dependent ERK phosphorylation, and corrected social learning deficits and impulsive behaviors in male Nf1+/– mice. Our results demonstrate that preventing the degradation of neurofibromin is a feasible and effective approach to ameliorate the neurodevelopmental phenotypes in a haploinsufficient disease model.

Authors

Su Jung Park, Jodi L. Lukkes, Ka-Kui Chan, Hayley P. Drozd, Callie B. Burgin, Shaomin Qian, Morgan McKenzie Sullivan, Cesar Gabriel Guevara, Nolen Cunningham, Stephanie Arenas, Makenna A. Collins, Jacob Zucker, JinHee Won, Abbi Smith, Li Jiang, Dana K. Mitchell, Steven D. Rhodes, Steven P. Angus, D. Wade Clapp

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Figure 1

F-box proteins FBXW11 and FBXO3 are involved in the degradation of neurofibromin.

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F-box proteins FBXW11 and FBXO3 are involved in the degradation of neuro...
(A) Control (Cont.) and F-box–specific siRNAs were transfected into human diploid fibroblasts. After 72 hours, lysates were prepared and used for immunoblotting to detect NF1 (top) and pERK1/2 (bottom doublet). Red font highlights increased neurofibromin levels in lysates prepared from wells containing siRNAs targeting FBXW11 or FBXO3. An siRNA targeting FBXW1A (bTrCP1, BTRC) was not included. (B) HeLa cells were transfected with a control siRNA or with siRNAs targeting FBXO3 or FBXW11. NF1, pERK1/2, and total ERK1/2 levels were analyzed 72 hours after transfection by immunoblotting. GAPDH was used as a loading control. (C) Left: CHX was added at a final concentration of 20 μg/mL to HeLa cells for the indicated durations prior to harvesting for immunoblotting to detect NF1. GAPDH was used as a loading control. Right: NF1 levels were quantified by densitometry relative to GAPDH. *P < 0.05, by 1-way ANOVA with Dunnett’s multiple-comparison test. Data indicate the mean ± SEM. (D) Left: HeLa cells were transfected with control siRNA or siRNA targeting FBXO3 or FBXW11. Sixty-eight hours after transfection, cells were treated with CHX (20 μg/mL final concentration) for 2 hours prior to harvesting and immunoblotting to detect NF1. GAPDH was used as a loading control. Right: NF1 levels were quantified by densitometry relative to GAPDH. *P < 0.05 comparing siCont with or without CHX, by unpaired 2-tailed t test. Data indicate the mean ± SEM.