The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation

Dunzendorfer-Matt, Theresia; Mercado, Ellen L.; Maly, Karl; McCormick, Frank; Scheffzek, Klaus

doi:10.1073/pnas.1607298113

Cited by 51 publications

(63 citation statements)

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“…We therefore asked whether the same genetic mechanisms that cause Rasopathies in humans also hold true for habituation deficits in Drosophila . In our screen, we tested habituation of two negative regulators of Ras: NF1 ( Drosophila Nf1) (55) and SPRED1 ( Drosophila Spred) (56, 57). Panneuronal knockdown of either regulator caused strong habituation deficits ( Figure 5D, in red ).…”

Section: Resultsmentioning

confidence: 99%

Integrative cross-species analyses identify deficits in habituation learning as a widely affected mechanism in Autism

Fencková

Asztalos

Cizek

et al. 2018

Preprint

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60Background: Although habituation is one of the most ancient and fundamental forms of learning, its 61 regulators and relevance for human disease are poorly understood. 62Methods: We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or 63 without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and tested 64 these models in light-off jump habituation. We dissected neuronal substrates underlying the 65 identified habituation deficits and integrated genotype-phenotype annotations, gene ontologies and 66 interaction networks to determine the clinical features and molecular processes that are associated 67 with habituation deficits. 68Results: We identified more than 100 genes required for habituation learning. For the vast majority 69 of these, 93 genes, a role in habituation learning was previously unknown. These genes characterize 70 ID disorders with macrocephaly/overgrowth and comorbid ASD. Moreover, ASD individuals from the 71 Simons Simplex Collection (SSC) carrying damaging de novo mutations in these genes exhibit 72 increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular 73 level, ID genes required for normal habituation are enriched in synaptic function and converge on 74Ras-MAPK signaling. Both increased Ras-MAPK signaling in GABAergic and decreased Ras-MAPK 75 signaling in cholinergic neurons specifically inhibit the adaptive habituation response. 76Conclusions: Our work supports the relevance of habituation learning to autism, identifies an 77 unprecedented number of novel habituation players, supports an emerging role for inhibitory 78 neurons in habituation and reveals an opposing, circuit-level-based mechanism for Ras-MAPK 79 signaling. This establishes habituation as a possible, widely applicable functional readout and target 80 for pharmacologic intervention in ID/ASD. 81 82 described in a fraction of ASD individuals (9-11), but has not been connected yet to specific genetic 96 defects, with a single exception. Recently, two independent studies demonstrated habituation 97 deficits in patients with Fragile X syndrome, the most common monogenic cause of intellectual 98 disability (ID) and ASD (12, 13), confirming previously reported habituation deficits in Fmr1 KO mice 99 (14, 15). Habituation deficits have also been reported in a limited number of other ID or ASD 100 (ID/ASD) disease models (16)(17)(18)(19). 101Because assessing human gene function in habituation is challenging, we utilized a cross-102 species approach. We apply light-off jump habituation in Drosophila to increase our knowledge on 103 the genetic control of habituation and, at the same time, to address the relevance of decreased 104 habituation in ID and in comorbid ASD disorders. Since ID is present in 70% of individuals with ASD 105 (20), monogenic causes of ID provide a unique molecular windows to ASD pathology (21). Drosophila 106 is a powerful, well-established model for ID (22)(23)(24) and offers genome-wide resources to st...

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Section: Resultsmentioning

confidence: 99%

Integrative cross-species analyses identify deficits in habituation learning as a widely affected mechanism in Autism

Fencková

Asztalos

Cizek

et al. 2018

Preprint

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“…The regions of neurofibromin that binds SPRED proteins comprise a discontinuous domain that flanks the GAP-related domain. SPRED binding does not affect neurofibromin’s GAP activity (Dunzendorfer-Matt et al, 2016) but is essential for enabling neurofibromin to downregulate RAS through recruitment to RAS in the plasma membrane.…”

Section: Ras and Human Diseasementioning

confidence: 99%

RAS Proteins and Their Regulators in Human Disease

Simanshu

Nissley

McCormick

2017

Cell

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1,388

1,350

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RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active. The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. All RAS biology occurs in membranes: a precise understanding of RAS’ interaction with membranes is essential to understand RAS action and to intervene in RAS-driven diseases.

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“…We therefore asked whether the same genetic mechanisms that cause Rasopathies in humans also hold true for habituation deficits in Drosophila. In our screen, we tested habituation of two negative regulators of Ras: neurofibromin 1 (Drosophila Nf1) (54) and Sprouty-related, EVH1 domain-containing protein 1 (Drosophila Spred) (55,56). Panneuronal knockdown of either regulator caused strong habituation deficits ( Figure 5D).…”

Section: A Key Role For Id and Asd-associated Ras Signaling In Habitumentioning

confidence: 99%

Habituation Learning Is a Widely Affected Mechanism in Drosophila Models of Intellectual Disability and Autism Spectrum Disorders

Fencková

Blok

Asztalos

et al. 2019

Biological Psychiatry

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BACKGROUND: Although habituation is one of the most ancient and fundamental forms of learning, its regulators and its relevance for human disease are poorly understood. METHODS: We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and we tested these models in light-off jump habituation. We dissected neuronal substrates underlying the identified habituation deficits and integrated genotype-phenotype annotations, gene ontologies, and interaction networks to determine the clinical features and molecular processes that are associated with habituation deficits. RESULTS: We identified .100 genes required for habituation learning. For 93 of these genes, a role in habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly and/or overgrowth and comorbid ASD. Moreover, individuals with ASD from the Simons Simplex Collection carrying damaging de novo mutations in these genes exhibit increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular level, ID genes required for normal habituation are enriched in synaptic function and converge on Ras/mitogen-activated protein kinase (Ras/MAPK) signaling. Both increased Ras/MAPK signaling in gamma-aminobutyric acidergic (GABAergic) neurons and decreased Ras/MAPK signaling in cholinergic neurons specifically inhibit the adaptive habituation response. CONCLUSIONS: Our work supports the relevance of habituation learning to ASD, identifies an unprecedented number of novel habituation players, supports an emerging role for inhibitory neurons in habituation, and reveals an opposing, circuit-level-based mechanism for Ras/MAPK signaling. These findings establish habituation as a possible, widely applicable functional readout and target for pharmacologic intervention in ID/ASD.

show abstract

The neurofibromin recruitment factor Spred1 binds to the GAP related domain without affecting Ras inactivation

Cited by 51 publications

References 50 publications

Integrative cross-species analyses identify deficits in habituation learning as a widely affected mechanism in Autism

Integrative cross-species analyses identify deficits in habituation learning as a widely affected mechanism in Autism

RAS Proteins and Their Regulators in Human Disease

Habituation Learning Is a Widely Affected Mechanism in Drosophila Models of Intellectual Disability and Autism Spectrum Disorders

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