Biology subjects

Botero, V.

Publications and source records attributed to Botero, V..

4 recordsLinked to original sources

bioRxiv2025

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

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, neu-rofibromin 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 downstream of Ras, which differentially affect metabolic and behavioral neurofibromatosis type 1 phenotypes.

neuroscience↗

bioRxiv2024

Neurofibromin deficiency alters the patterning and prioritization of motor behaviors in a state-dependent manner

Genetic disorders such as neurofibromatosis type 1 increase vulnerability to cognitive and behavioral disorders, such as autism spectrum disorder and attention-deficit/hyperactivity disorder. Neurofibromatosis type 1 results from loss-of-function mutations in the neurofibromin gene and subsequent reduction in the neurofibromin protein (Nf1). While the mechanisms have yet to be fully elucidated, loss of Nf1 may alter neuronal circuit activity leading to changes in behavior and susceptibility to cognitive and behavioral comorbidities. Here we show that mutations decreasing Nf1 expression alter motor behaviors, impacting the patterning, prioritization, and behavioral state dependence in a Drosophila model of neurofibromatosis type 1. Loss of Nf1 increases spontaneous grooming in a nonlinear spatial and temporal pattern, differentially increasing grooming of certain body parts, including the abdomen, head, and wings. This increase in grooming could be overridden by hunger in food-deprived foraging animals, demonstrating that the Nf1 effect is plastic and internal state-dependent. Stimulus-evoked grooming patterns were altered as well, with nf1 mutants exhibiting reductions in wing grooming when coated with dust, suggesting that hierarchical recruitment of grooming command circuits was altered. Yet loss of Nf1 in sensory neurons and/or grooming command neurons did not alter grooming frequency, suggesting that Nf1 affects grooming via higher-order circuit alterations. Changes in grooming coincided with alterations in walking. Flies lacking Nf1 walked with increased forward velocity on a spherical treadmill, yet there was no detectable change in leg kinematics or gait. Thus, loss of Nf1 alters motor function without affecting overall motor coordination, in contrast to other genetic disorders that impair coordination. Overall, these results demonstrate that loss of Nf1 alters the patterning and prioritization of repetitive behaviors, in a state-dependent manner, without affecting motor coordination.

neuroscience↗

bioRxiv2022

Neurofibromin 1 mediates sleep depth in Drosophila

Neural regulation of sleep and metabolic homeostasis are critical in many aspects of human health. Despite extensive epidemiological evidence linking sleep dysregulation with obesity, diabetes, and metabolic syndrome, little is known about the neural and molecular basis for the integration of sleep and metabolic function. The RAS GTPase-activating gene Neurofibromin (Nf1) has been implicated in the regulation of sleep and metabolic rate, raising the possibility that it serves to integrate these processes, but the effects on sleep consolidation and physiology remain poorly understood. A key hallmark of sleep depth in mammals and flies is a reduction in metabolic rate during sleep. Here, we use indirect calorimetry to define the role of Nf1 on sleep-dependent changes in metabolic rate. Flies lacking Nf1 fail to suppress metabolic rate during sleep, raising the possibility that loss of Nf1 prevents flies from integrating sleep and metabolic state. Sleep of Nf1 mutant flies is fragmented with a reduced arousal threshold in Nf1 mutants, suggesting Nf1 flies fail to enter deep sleep. The effects of Nf1 on sleep can be localized to a subset of neurons expressing the GABA receptor Rdl. Selective knockdown of Nf1 in Rdl-expressing neurons increases gut permeability and reactive oxygen species (ROS) in the gut, suggesting a critical role for deep sleep in gut homeostasis. Together, these findings suggest Nf1 acts in GABA-sensitive neurons to modulate sleep depth in Drosophila.

neuroscience↗

bioRxiv2019

Neurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila

Neurofibromatosis type 1 (NF1) is a genetic disorder predisposing patients to a range of features, the most characteristic of which include areas of abnormal skin pigmentation and benign tumors associated with peripheral nerves, termed neurofibromas. Less common, but more serious symptoms also include malignant peripheral nerve sheath tumors, other malignancies, and learning disabilities. The NF1 gene encodes neurofibromin, a large protein that functions as a negative regulator of Ras signaling and mediates pleiotropic cellular and organismal function. Recent evidence suggests NF1 may regulate metabolism, though the mechanisms are unknown. Here we show that the Drosophila ortholog of NF1, dNf1 regulates metabolic homeostasis in fruit flies by functioning within a discrete brain circuit. Loss of dNf1 increases metabolic rate and feeding, enhances starvation susceptibility, and decreases lipid stores while increasing lipid turnover rate. The increase in metabolic rate is independent of locomotor activity (grooming), and maps to a subset of neurons in the ventral nervous system. The feeding and metabolic rate effects are due to loss of dNf1 in the same set of neurons, suggesting that increased feeding may be a compensatory effect driven by the increase in metabolic rate and lipid turnover. Finally, we show that the Ras GAP-related domain of neurofibromin is required for normal metabolism, demonstrating that Ras signaling downstream of dNf1 mediates the metabolic effects. These data demonstrate that dNf1 regulates metabolic rate via neuronal mechanisms, suggest that cellular and systemic metabolic alterations may represent a pathophysiological mechanism in NF1, and provide a platform for investigating the cellular role of neurofibromin in metabolic homeostasis.

neuroscience↗