Fact-checked by Grok 2 weeks ago

Neurofibromin

Neurofibromin is a large, multifunctional protein encoded by the NF1 located on 17q11.2, consisting of 2818 and serving primarily as a GTPase-activating protein (GAP) that negatively regulates the /MAPK signaling pathway to inhibit and promote . Mutations in NF1, which occur in approximately 1 in 3,000 individuals worldwide, lead to type 1 (NF1), an autosomal dominant disorder characterized by the development of benign and malignant tumors, café-au-lait spots, skeletal abnormalities, and learning disabilities due to loss of neurofibromin's regulatory functions. The protein's structure includes key domains such as the cysteine-serine-rich domain (CSRD), the GAP-related domain (GRD) responsible for interaction, a Sec14-like phospholipid-binding domain (SecPH), and a C-terminal domain (CTD) involved in additional signaling. Beyond Ras inactivation, neurofibromin modulates multiple pathways, including PI3K/AKT/ for cell survival, Rho//LIMK2/cofilin for cytoskeletal dynamics and migration, and cAMP/ for neuronal processes like neurite outgrowth and homeostasis. These functions are particularly critical in neurons, Schwann cells, and , where neurofibromin is highly expressed, contributing to its role in development and maintenance. In NF1 disease, over 1,000 distinct NF1 mutations—often resulting in truncated or absent protein—cause hyperactivation of and downstream effectors, driving tumorigenesis such as plexiform neurofibromas, malignant peripheral nerve sheath tumors (MPNSTs), and optic gliomas, as well as non-tumor manifestations like cognitive impairments linked to dysregulation. Therapeutically, targeting neurofibromin-related pathways has shown promise; for instance, the MEK inhibitors (FDA-approved as of September 2025 for pediatric patients aged 1 year and older) and mirdametinib (FDA-approved as of February 2025 for adults and pediatric patients aged 2 years and older) are approved for symptomatic, inoperable plexiform neurofibromas in NF1, while emerging strategies explore and Ras modulators to address the syndrome's heterogeneity. Ongoing research into neurofibromin's post-translational modifications, such as and ubiquitination, further elucidates its regulation and potential as a therapeutic target.

Gene

Location and Structure

The NF1 gene, which encodes neurofibromin, is located on the long arm of human chromosome 17 at the q11.2 cytogenetic band. It spans approximately 280 kb of genomic DNA, encompassing a complex structure that includes multiple intragenic elements such as three embedded genes (OMGP, EVI2A, and EVI2B) and a pseudogene (AK3L1). The gene comprises 58 exons in its primary transcript, with the full-length coding sequence assembled from 57 constitutive exons plus additional alternatively spliced segments. The exon-intron organization of NF1 is characterized by notably large introns, some exceeding 100 kb, which account for much of the gene's extensive genomic footprint. occurs at specific sites, including exons 9a/9br (nervous system-specific), 10a-10b, 23a (within the GAP-related domain), and 48a (muscle-specific), generating isoform diversity while the canonical transcript maintains an of 8,454 nucleotides that translates to a 2,818-amino-acid protein. Evolutionary conservation of NF1 is evident across mammals, with the human gene sharing 92% nucleotide identity and 98% amino acid identity in the with its ortholog, reflecting its essential role in ras signaling regulation. The gene's large size, combined with abundant repetitive elements like Alu sequences and processed pseudogenes distributed throughout introns, contributes to its exceptionally high mutation rate, estimated at 10 times that of average human genes.

Regulatory Elements

The promoter region of the NF1 gene is TATA-less and lacks a discernible CCAAT box, relying instead on a GC-rich sequence with multiple transcription start sites for initiation of transcription. This structure is embedded within a classic CpG island that extends from the proximal promoter into , facilitating basal transcription in various types. The promoter contains binding sites for transcription factors such as SP1, CREB, and AP2, which contribute to its regulatory activity. The 3' untranslated region (3' UTR) of the NF1 mRNA spans approximately 3.5 kb and includes AU-rich elements () that bind proteins like HuR, promoting mRNA instability and turnover. These act as negative regulators of transcript stability, influencing neurofibromin expression levels. Additionally, the 3' UTR features two polyadenylation signals, enabling alternative that can modulate mRNA length and stability. Enhancer elements for the NF1 gene have been identified both proximally (~42 kb upstream) and distally (~600 kb upstream), often located in H3K27ac-enriched regions indicative of active enhancers. These regions contain binding motifs for factors like p300, c-Fos, and c-Jun, supporting tissue-specific modulation of NF1 expression. Epigenetic regulation of the NF1 promoter involves patterns, particularly hypermethylation of CpG sites that correlates with in neurofibromas and other NF1-associated tumors. Such methylation can inhibit binding of transcription factors like SP1 and CREB, reducing NF1 expression in tumor contexts. The CpG island in the promoter is typically hypomethylated in normal cells, highlighting the role of aberrant methylation in disease progression.

Mutations

The NF1 gene, which encodes neurofibromin, is highly mutable due to its large size and repetitive sequences, resulting in over 5,000 distinct disease-causing variants reported as of 2024. Common mutation types include , which account for approximately 40% of cases and introduce premature termination codons leading to truncated proteins; frameshift mutations, comprising about 30% and caused by small insertions or deletions that disrupt the ; splicing mutations, representing 10-20% and altering exon-intron boundaries; missense mutations, around 5-10% and substituting single ; and large deletions encompassing the entire gene or multiple exons, occurring in 5-11% of cases. These variants are cataloged in specialized databases such as the Human Gene Mutation Database (HGMD) and the Leiden Open Variation Database (LOVD), which provide comprehensive repositories for variant annotation and frequency data. Approximately 50% of NF1 mutations arise , making affected cases sporadic rather than inherited, while the remaining 50% are transmitted from an affected parent. mutations exhibit a strong paternal , with over 80% originating on the paternal , likely due to higher mutation rates in influenced by advanced paternal age. Genotype-phenotype correlations have been observed for certain NF1 variants, particularly large microdeletions spanning 1.4 Mb (type-1 deletions) that encompass the NF1 gene and flanking regions, which are associated with a more severe disease presentation including distinctive facial features and increased tumor burden compared to intragenic point mutations. In contrast, specific missense variants, such as p.Met992del, correlate with milder manifestations. Many NF1 mutations, especially nonsense and frameshift types introducing premature stop codons, trigger (NMD), a surveillance mechanism that degrades aberrant mRNA transcripts, thereby further reducing functional neurofibromin protein levels. This process affects up to 20% of cases with nonsense mutations, exacerbating the loss-of-function .

Protein

Structure

Neurofibromin is a large multidomain protein consisting of 2818 and having a calculated molecular weight of approximately 320 kDa. Encoded by the NF1 gene located on chromosome 17q11.2, it exhibits a complex domain architecture that includes several functionally distinct regions. The protein's N-terminal region encompasses a cysteine-serine-rich domain (CSRD) spanning residues 543 to 909, which is characterized by multiple pairs and serine residues potentially involved in . Following the CSRD, neurofibromin features a tubulin-binding domain (TBD) from residues 1095 to 1197. The central portion contains the GAP-related domain (GRD), extending from residues 1198 to 1549, a key catalytic module homologous to Ras-GTPase-activating proteins. Crystal structures of the GRD, such as PDB entry 1NF1 (residues 1198–1530), reveal a compact fold with alpha-helices and beta-sheets forming the Ras-binding interface, including an arginine finger residue critical for GTP stimulation. Additional structures, like PDB 6OB3, depict the GRD in complex with , highlighting the helical arginine finger insertion into the nucleotide-binding pocket. Toward the C-terminus, neurofibromin includes the Sec-PH tandem domain, comprising a Sec14-like module (residues 1560–1698) and a pleckstrin homology (PH) domain (residues 1699–1835), which together form a lipid-binding module. The overall architecture also incorporates a C-terminal domain (CTD) from residues 2260 to 2818, which includes a syndecan-binding region (residues 2619–2719) facilitating interactions with components. Significant portions of neurofibromin, particularly in the interdomain linkers, are predicted to be intrinsically disordered, contributing to its flexibility and regulatory potential. Secondary structure predictions indicate alpha-helical content predominantly within the GRD and Sec-PH domains, with beta-strands supporting the core folds in these regions.

Function

Neurofibromin primarily functions as a Ras-specific GTPase-activating protein (Ras-GAP), catalyzing the of GTP to GDP on proteins and thereby inactivating them to prevent excessive signaling. This activity is mediated by its GAP-related domain (GRD), which inserts an arginine finger (Arg1276) into the nucleotide-binding pocket of Ras-GTP, stabilizing the and accelerating the intrinsic GTP hydrolysis rate by approximately 10^5-fold. By negatively regulating , neurofibromin suppresses downstream activation of the MAPK/ERK pathway, which otherwise promotes , , and survival. Beyond its canonical Ras-GAP role, neurofibromin modulates signaling through interactions with adenylate cyclases, enhancing their activity to increase intracellular levels in a manner that can be independent of regulation. This modulation influences (PKA) activation, which in turn affects cytoskeleton dynamics by phosphorylating targets involved in cytoskeletal reorganization. Additionally, neurofibromin regulates architecture via Rho pathways, impacting cell motility and morphology. Neurofibromin also exhibits non- functions in modulating the pathway through crosstalk with PI3K/Akt signaling, influencing cellular growth and metabolism. Key protein interactions facilitate these roles; for instance, neurofibromin binds to SPRED1 via its GRD, recruiting the complex to the plasma membrane to potentiate Ras inactivation and fine-tune MAPK signaling. Furthermore, neurofibromin associates with , potentially aiding its subcellular localization and contributing to cytoskeletal regulation. Loss of neurofibromin function leads to sustained Ras-GTP accumulation, resulting in hyperactive downstream pathways and uncontrolled cellular proliferation characteristic of tumorigenesis.

Isoforms

Neurofibromin exists in multiple isoforms generated primarily through of the NF1 pre-mRNA, with the two major variants, Type I and Type II, arising from the inclusion or exclusion of 23a within the GTPase-activating protein (GAP)-related domain (GRD). Type I neurofibromin, the full-length isoform lacking the 63-nucleotide 23a insertion, is ubiquitously expressed across tissues and serves as the predominant form in most cell types, including non-neuronal cells. In contrast, Type II neurofibromin includes 23a, resulting in a 21-amino-acid insertion that alters the GRD structure; this isoform is enriched in neuronal tissues, particularly in the central and peripheral nervous systems, such as Schwann cells and brain regions. Additional isoforms stem from alternative splicing at other sites, notably exon 48a, which introduces a 54-nucleotide insertion near the when included, adding 18 and producing Type III neurofibromin. This variant is predominantly expressed in muscle and cardiac tissues, with tissue-specific distribution reflecting developmental roles in . A fourth isoform, Type IV, incorporates both exon 23a and exon 48a, though it is less commonly detected and similarly restricted to specific tissues like heart and . Skipping of exon 48a in the canonical transcript maintains the standard C-terminal domain without this extension, influencing isoform stability and localization in non-muscle cells. Functionally, Type I exhibits robust -GAP activity, efficiently hydrolyzing GTP on to suppress signaling, whereas Type II displays reduced GAP activity due to the 23a insertion disrupting optimal GRD conformation, potentially allowing finer regulation of -ERK pathways in neurons. Despite this, Type II supports specialized neuronal functions, including modulation of learning behaviors and , independent of full GAP potency. The C-terminal variants from 48a splicing, such as Type III, may enhance interactions with cytoskeletal elements or contribute to myogenic , though their GAP activities remain comparable to Type I. Isoforms are detected using analysis with antibodies targeting distinct epitopes, revealing band shifts: Type I migrates at approximately 250-280 kDa, while Type II appears slightly larger (around 260-290 kDa) due to the insertion, and C-terminal variants like Type III show further mobility differences. Isoform-specific RT-PCR or quantitative assays further confirm tissue-enriched expression patterns. The generating these isoforms, particularly 23a inclusion/exclusion, is highly conserved across vertebrates, including mice, rats, chickens, and cows, underscoring its evolutionary importance for tissue-specific neurofibromin functions. This conservation extends to the 48a , present in mammals and , suggesting adaptive roles in diverse physiological contexts.

Regulation

Neurofibromin, the protein product of the NF1 gene, undergoes C-to-U primarily in its mRNA transcripts within 29, where an codon (CGA) is deaminated to a uracil-containing (UGA). This editing event is catalyzed by mRNA editing enzyme catalytic polypeptide 1 (APOBEC1) and its associated cofactors, leading to premature translational termination and production of a truncated neurofibromin isoform lacking the C-terminal region. The resulting protein exhibits diminished Ras-GTPase activating protein (Ras-GAP) activity compared to the full-length form, as the truncation disrupts domains involved in Ras . This editing is predominantly observed in tumor tissues from patients with neurofibromatosis type 1 (NF1), such as schwannomas and neurofibrosarcomas, with editing efficiency varying from low levels in benign neurofibromas (approximately 1-5%) to higher levels in malignant peripheral nerve sheath tumors (up to approximately 12%). In normal tissues, editing is minimal or absent, suggesting a tissue-specific regulatory mechanism potentially linked to factors that recruit APOBEC1 complexes to NF1 transcripts. Functional assays in cell lines transfected with edited NF1 constructs demonstrate that the truncated isoform fails to suppress Ras-mediated , contributing to enhanced oncogenic signaling in edited cells. Sequencing studies of NF1 mRNA from patient-derived tumors have confirmed the editing site through direct detection of the C-to-U change, with quantitative RT-PCR and Western blotting showing correlated reductions in full-length neurofibromin protein levels. In NF1-associated malignancies, reduced efficiency or absence of the enzyme complex correlates with less aggressive phenotypes, highlighting as a modifier of disease progression; for instance, tumors with high exhibit increased sensitivity to Ras pathway inhibitors in preclinical models. This thus represents a regulatory layer that exacerbates NF1 in neoplastic contexts, independent of mutations.

Post-translational Modifications

Neurofibromin undergoes multiple post-translational modifications that modulate its stability, localization, and GTPase-activating activity toward . Mass spectrometry-based phosphoproteomics has identified multiple sites across the protein, highlighting the extensive regulatory potential of this modification. occurs at numerous sites, primarily regulated by kinases such as (), () isoforms, AKT, and (). For instance, serine 2808 (S2808) in the C-terminal domain (CTD) is phosphorylated by -ε in a cell cycle-dependent manner, promoting nuclear localization of neurofibromin. In the cysteine-serine-rich domain (CSRD), and target sites that facilitate binding to 14-3-3 proteins and modulate GAP activity. phosphorylation in the CSRD enhances Ras-GAP activity. Ubiquitination primarily involves K48-linked chains that target neurofibromin for proteasomal degradation, thereby controlling its protein levels. This process is mediated by several ubiquitin ligases. SUMOylation affects neurofibromin localization and activity, with key sites including lysines 1383 and 1385 in 23a, as well as K1634 (minor) and K1731 (major) in the SecPH domain. The K1731 site modulates Ras-GAP activity, and to (K1731R) reduces this function. These modifications often target specific domains, such as the GRD and CTD, to fine-tune neurofibromin's interactions and signaling output.

Clinical Significance

Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is a multisystem primarily caused by loss-of-function mutations in the NF1 gene, which encodes the protein neurofibromin, a negative regulator of the signaling pathway. These mutations typically result in , where a single functional copy of the gene is insufficient to maintain normal neurofibromin levels, leading to uncontrolled cell growth and tumor formation. NF1 follows an autosomal dominant inheritance pattern, with nearly complete ; each child of an affected individual has a 50% chance of inheriting the mutation. The disorder has a prevalence of approximately 1 in 2,500 to 3,000 individuals worldwide. While mutations are present in all cells, tumor development often requires a "second hit" , frequently through (LOH) in the wild-type NF1 allele, promoting biallelic inactivation in affected tissues. The clinical manifestations of NF1 are highly variable but characteristically include multiple café-au-lait macules (flat, pigmented skin spots greater than 5 mm in children or 15 mm in adults), which are often the earliest sign appearing in infancy. Other common features encompass cutaneous and subcutaneous neurofibromas (benign tumors arising from peripheral nerves), axillary or inguinal freckling, Lisch nodules (iris hamartomas visible on slit-lamp examination), optic pathway gliomas (low-grade tumors affecting vision in about 15% of cases), and skeletal abnormalities such as skeletal dysplasia (including , tibial pseudarthrosis, and orbital bone defects). Additional complications may involve learning disabilities, , and cardiovascular issues, contributing to the disorder's multisystem impact. Diagnosis of NF1 relies on established clinical criteria established by the (NIH) consensus, requiring the presence of at least two of the following seven features: six or more café-au-lait macules of specified size; two or more s of any type or one plexiform neurofibroma; axillary or inguinal freckling; an optic ; two or more Lisch nodules; a distinctive osseous lesion such as sphenoid dysplasia or tibial pseudarthrosis; or a first-degree relative with NF1 meeting these criteria. These criteria are highly sensitive and specific, particularly after age 5, though for NF1 mutations can confirm diagnosis in equivocal cases, identifying pathogenic variants in over 95% of clinically diagnosed individuals. A hallmark of NF1's tumor spectrum is the development of plexiform neurofibromas, complex, infiltrative benign tumors that occur in 30-50% of patients and can cause significant morbidity through compression of nearby structures, , and . These tumors arise early in life and may undergo . Individuals with NF1 also face an elevated lifetime risk of malignant peripheral nerve sheath tumors (MPNSTs), aggressive sarcomas with an incidence of 8-13%, representing the leading cause of mortality in this population. Recent updates in NF1 , including 2025 consensus recommendations, emphasize enhanced for malignant progression, particularly in plexiform neurofibromas, through regular clinical assessments, whole-body MRI starting in childhood, and multidisciplinary care to detect early transformation to MPNSTs via symptoms like rapid growth or pain. These guidelines advocate for targeted therapies, such as MEK inhibitors; for example, mirdametinib (Gomekli) was FDA-approved in 2025 for adults and pediatric patients aged ≥2 years with symptomatic, inoperable plexiform neurofibromas, showing response rates of 41% in adults and 52% in pediatric patients in clinical trials.

Other Associated Conditions

Neurofibromin, encoded by the NF1 gene, plays a role in several conditions beyond the core manifestations of neurofibromatosis type 1 (NF1), primarily through its tumor suppressor function in the /MAPK pathway. Juvenile myelomonocytic (JMML) is associated with NF1 mutations, occurring in approximately 10-15% of JMML cases, where biallelic inactivation of NF1 drives leukemogenesis in affected children. Women with NF1 face an elevated risk of , with studies indicating a 3- to 5-fold increase before age 50 and a cumulative incidence of 8.4% by age 50 compared to 2% in the general population, often linked to loss of neurofibromin-mediated regulation. Watson syndrome, characterized by , café-au-lait spots, and mild intellectual impairment, arises from specific NF1 mutations and is considered allelic to NF1, representing a milder variant with overlapping features. Somatic mutations in NF1 contribute to tumorigenesis in various sporadic cancers independent of germline NF1. These alterations are frequent in melanomas (up to 15% of cases), where they promote hyperactivation and aggressive phenotypes, and in glioblastomas, where NF1 loss defines the mesenchymal subtype and correlates with poor prognosis. In other tumors such as lung adenocarcinomas and ovarian cancers, somatic NF1 inactivation occurs in about 5% of cases, enhancing tumor heterogeneity and resistance to therapies like MEK inhibitors. Neurofibromin deficiency is linked to neurodevelopmental disorders in up to 50-60% of individuals with NF1. Learning disabilities, particularly in reading, , and visuospatial skills, affect about half of children with NF1 due to disrupted neuronal signaling. Attention-deficit/hyperactivity disorder (ADHD) occurs in 40-50% of cases, often with hyperactivity and inattention stemming from altered pathway activity in the brain. Overlaps with autism spectrum disorder () are notable, with ASD diagnosed in 25% of NF1 patients, independent of cognitive impairments, and involving social communication deficits. Recent research highlights neurofibromin's influence on metabolic homeostasis. Loss of Nf1 in mouse models increases metabolic rate, enhances glucose clearance, and confers resistance to diet-induced obesity, reducing fat mass through neuronal mechanisms that elevate energy expenditure. In humans, NF1 is associated with cardiovascular anomalies, including pulmonic stenosis and hypertension, particularly in variants resembling Noonan syndrome. Neurofibromatosis-Noonan syndrome, a distinct NF1 subtype caused by specific NF1 mutations, features short stature, pectus excavatum, and congenital heart defects like pulmonary valve stenosis in nearly all cases.

Model Organisms

Mouse Models

Mouse models of neurofibromin deficiency have been pivotal in elucidating the role of Nf1 gene mutations in neurofibromatosis type 1 (NF1) pathogenesis. Conventional germline knockout of Nf1 results in homozygous Nf1^{-/-} embryos that are lethal around embryonic day 11.5 to 13.5, exhibiting cardiovascular abnormalities such as double outlet right ventricle and edema, as well as neural defects including exencephaly. Heterozygous Nf1^{+/-} mice are viable and fertile but predisposed to tumor formation, developing pheochromocytomas, neurofibromas, and juvenile myeloid leukemias by 12 to 18 months of age, thereby mimicking the tumor spectrum observed in human NF1 patients. These heterozygotes also display non-neoplastic phenotypes, including increased astrocyte proliferation, astrogliosis, and spatial learning deficits in hippocampal-dependent tasks. To overcome the embryonic lethality of complete Nf1 loss and achieve tissue-specific inactivation, conditional knockout models employing Nf1^{flox/flox} alleles crossed with drivers have been widely utilized. For instance, Nestin-Cre-mediated deletion in neural progenitor cells produces optic pathway gliomas in the and , recapitulating low-grade astrocytomas seen in NF1 and revealing mechanisms of gliomagenesis driven by neurofibromin deficiency in and . Other drivers, such as GFAP-Cre for or Dhh-Cre for Schwann cell precursors, induce plexiform neurofibromas, highlighting the cell-of-origin specificity in peripheral development. These models have demonstrated that biallelic Nf1 inactivation in specific lineages is necessary for tumor initiation, while heterozygous backgrounds enhance susceptibility through microenvironmental effects. Compound mutant models combining Nf1 loss with inactivation of cooperating tumor suppressors, such as Trp53, have accelerated the study of malignant progression. In the NP-Plp model, postnatal tamoxifen-inducible deletion of Nf1 and Trp53 in Schwann cells using Plp-CreER yields malignant peripheral nerve sheath tumors (MPNSTs) with 100% penetrance by 4 to 9 months, exhibiting histological features like spindle cell morphology and transcriptomic profiles akin to human MPNSTs, including partial loss of H3K27me3. This synergy underscores p53 as a key modifier that promotes malignant transformation in Nf1-deficient cells, enabling rapid preclinical testing of therapies. These models collectively exhibit NF1-relevant phenotypes beyond tumors, such as optic gliomas responsive to microenvironmental cues and cognitive impairments like impaired visuospatial learning, which parallel human clinical features. Recent advances as of 2025 include /Cas9-edited models for precise Nf1 mutations; for example, embryo of Cas9 ribonucleoproteins has generated heterozygous knockouts with targeted indels, facilitating studies of patient-specific variants and somatic tumorigenesis in peripheral nerves.

Drosophila Models

In Drosophila melanogaster, the ortholog of neurofibromin is encoded by the dNf1 gene, which produces a large protein of approximately 310 kDa consisting of 2,803 and exhibiting about 60% sequence identity to the human protein across its length. This fly neurofibromin retains a highly conserved GTPase-activating protein-related domain (GRD) that functions similarly to negatively regulate signaling by accelerating GTP . Unlike vertebrates with multiple neurofibromin isoforms, dNf1 generates five alternatively spliced isoforms, with the longest (Nf1-PA) serving as the primary functional form in neural tissues. Null mutants of dNf1 are homozygous viable, lacking the larval lethality observed in some higher organisms, but they display pronounced phenotypes including reduced body size, disrupted circadian rhythms, and impaired associative learning and . These defects arise primarily from hyperactivation of the /MAPK pathway due to loss of GRD-mediated activity, though additional non-Ras functions, such as modulation of /PKA signaling, contribute to growth and behavioral impairments. For instance, dNf1 null flies show deficits in olfactory learning tasks, where performance is reduced by up to 50% compared to wild-type controls, reflecting conserved roles in neuronal . To dissect tissue-specific roles, researchers employ the combined with (RNAi) for targeted knockdown of dNf1. Pan-neuronal RNAi recapitulates null mutant phenotypes, such as learning deficits and sleep fragmentation, while neuron subtype-specific knockdown—particularly in cells—reveals circuit-level contributions to inhibitory signaling and mushroom body function. At the , dNf1 loss leads to synaptic overgrowth and altered vesicle release, indicating roles in confining synapse expansion via focal adhesion (FAK) signaling, though direct disruptions remain less characterized. These models highlight conserved mechanisms of neurofibromin in regulation across species, providing simpler genetic contexts than mammalian systems for mechanistic studies; for example, dNf1 mutants have facilitated high-throughput drug screens identifying like TAE684 to rescue learning impairments.