scholarly journals Modulation of cAMP and Ras Signaling Pathways Improves Distinct Behavioral Deficits in a Zebrafish Model of Neurofibromatosis Type 1

Cell Reports ◽  
2014 ◽  
Vol 8 (5) ◽  
pp. 1265-1270 ◽  
Author(s):  
Marc A. Wolman ◽  
Eric D. de Groh ◽  
Sean M. McBride ◽  
Thomas A. Jongens ◽  
Michael Granato ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Ras Signaling ◽  
Zebrafish Model ◽  
Behavioral Deficits

Ras-Related Signaling Pathways in Valve Development: Ebb and Flow

Physiology ◽  
2005 ◽  
Vol 20 (6) ◽  
pp. 390-397 ◽  
Author(s):  
Katherine E. Yutzey ◽  
Melissa Colbert ◽  
Jeffrey Robbins
Keyword(s):  
Signaling Pathways ◽  
Congenital Heart ◽  
Molecular Mechanisms ◽  
Heart Defects ◽  
Neurofibromatosis Type ◽  
Ras Signaling ◽  
Live Births ◽  
Valve Development ◽  
Insight Into

Congenital heart defects affect ~1 in every 100 live births, and deficits in the formation of the mitral, tricuspid, and outflow tract valves account for 20–25% of all cardiac malformations. Mutations in genes that affect Ras signaling have been identified in individuals with congenital valve disease associated with Noonan syndrome and neurofibromatosis type 1. Dissection of Ras-related signaling pathways during valvulogenesis provides seminal insight into cellular and molecular mechanisms that contribute to congenital heart disease.

scholarly journals Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications

2010 ◽  
Vol 28 (1) ◽  
pp. E8 ◽  
Author(s):  
Oren N. Gottfried ◽  
David H. Viskochil ◽  
William T. Couldwell
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Neurofibromatosis Type ◽  
Germline Mutations ◽  
Tumor Formation ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Peripheral Nerve Sheath Tumors

Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular neurofibroma tumors, and less frequently by malignant peripheral nerve sheath tumors (MPNSTs) and optic nerve gliomas. Significant advances have been made in elucidating the cellular, genetic, and molecular biology involved in tumor formation in NF1. Neurofibromatosis Type 1 is caused by germline mutations of the NF1 tumor suppressor gene, which generally result in decreased intracellular neurofibromin protein levels, leading to increased cascade Ras signaling to its downstream effectors. Multiple key pathways are involved with the development of tumors in NF1, including Ras/mitogen-activated protein kinase (MAPK) and Akt/mammalian target of rapamycin (mTOR). Interestingly, recent studies demonstrate that multiple other developmental syndromes (in addition to NF1) share phenotypic features resulting from germline mutations in genes responsible for components of the Ras/MAPK pathway. In general, a somatic loss of the second NF1 allele, also referred to as loss of heterozygosity, in the progenitor cell, either the Schwann cell or its precursor, combined with haploinsufficiency in multiple supporting cells is required for tumor formation. Importantly, a complex series of interactions with these other cell types in neurofibroma tumorigenesis is mediated by abnormal expression of growth factors and their receptors and modification of gene expression, a key example of which is the process of recruitment and involvement of the NF1+/– heterozygous mast cell. In general, for malignant transformation to occur, there must be accumulation of additional mutations of multiple genes including INK4A/ARF and P53, with resulting abnormalities of their respective signal cascades. Further, abnormalities of the NF1 gene and molecular cascade described above have been implicated in the tumorigenesis of NF1 and some sporadically occurring gliomas, and thus, these treatment options may have wider applicability. Finally, increased knowledge of molecular and cellular mechanisms involved with NF1 tumorigenesis has led to multiple preclinical and clinical studies of targeted therapy, including the mTOR inhibitor rapamycin, which is demonstrating promising preclinical results for treatment of MPNSTs and gliomas.

scholarly journals Isoform-specific NF1 mRNA levels correlate with disease severity in Neurofibromatosis type 1

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Antonia Assunto ◽  
Ursula Ferrara ◽  
Alessandro De Luca ◽  
Claudia Pivonello ◽  
Lisa Lombardo ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Neurofibromatosis Type 1 ◽  
Phenotypic Variability ◽  
Neurofibromatosis Type ◽  
Protein Isoforms ◽  
Ras Signaling ◽  
Mrna Levels ◽  
Mrna Isoforms ◽  
Transcript Processing

Abstract Background Neurofibromatosis type 1 (NF1) is characterized by an extreme clinical variability both within and between families that cannot be explained solely by the nature of the pathogenic NF1 gene mutations. A proposed model hypothesizes that variation in the levels of protein isoforms generated via alternative transcript processing acts as modifier and contributes to phenotypic variability. Results Here we used real-time quantitative PCR to investigate the levels of two major NF1 mRNA isoforms encoding proteins differing in their ability to control RAS signaling (isoforms I and II) in the peripheral blood leukocytes of 138 clinically well-characterized NF1 patients and 138 aged-matched healthy controls. As expected, expression analysis showed that NF1 isoforms I and II levels were significantly lower in patients than controls. Notably, these differences were more evident when patients were stratified according to the severity of phenotype. Moreover, a correlation was identified when comparing the levels of isoform I mRNA and the severity of NF1 features, with statistically significant lower levels associated with a severe phenotype (i.e., occurrence of learning disability/intellectual disability, optic gliomas and/or other neoplasias, and/or cerebrovascular disease) as well as in patients with cognitive impairment. Conclusions The present findings provide preliminary evidence for a role of circuits controlling NF1 transcript processing in modulating NF1 expressivity, and document an association between the levels of neurofibromin isoform I mRNA and the severity of phenotype and cognitive impairment in NF1.

scholarly journals EXTH-08. MINIPIG MODELS OF NEUROFIBROMATOSIS TYPE 1 FOR THERAPEUTIC DEVELOPMENT

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii88-ii88
Author(s):  
Adrienne Watson ◽  
Sara Osum ◽  
Mandy Taisto ◽  
Barbara Tschida ◽  
Dylan Duerre ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Nonsense Mutation ◽  
Plasma Concentrations ◽  
Neurofibromatosis Type ◽  
Mapk Signaling ◽  
Optic Pathway Glioma ◽  
Ras Signaling ◽  
Safety And Efficacy ◽  
Mek Inhibitors

Abstract Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in the neurofibromin 1 (NF1) gene. NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. Using gene-editing technology, we have developed a minipig model of NF1 that exhibits clinical hallmarks of the disease, including café au lait macules, neurofibromas, and optic pathway glioma. We have conducted pharmacological studies in our NF1 minipigs to assess the pharmacokinetic and pharmacodynamic properties of MEK inhibitors for NF1. We have demonstrated that oral administration of several MEK inhibitors results in clinically relevant plasma concentrations and consequent inhibition of Ras signaling in immune cells, and certain MEK inhibitors can cross the blood brain barrier and have a pharmacodynamic effect, suggesting that they may be effective in treating NF1-associated brain tumors. Because over 20% of NF1 patients harbor NF1 nonsense mutations, we are assessing safety and efficacy of nonsense mutation suppressors that may be effective in treating NF1. We evaluated six drugs known to induce nonsense mutation suppression in several primary cell types isolated from NF1 minipigs and show that several of these drugs have the propensity to induce the production of full length neurofibromin protein, leading to a subsequent reduction in MAPK signaling. Information acquired from this NF1 minipig preclinical model will be leveraged towards initiating a clinical trial in NF1 patients. The NF1 minipig provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1 therapies.

scholarly journals Malignant Peripheral Nerve Sheath Tumor in an Army Reservist With Neurofibromatosis Type 1

2020 ◽  
Author(s):  
Chung-Ting J Kou ◽  
Matthew Rendo ◽  
Devin R Broadwater ◽  
Bradley Beeler
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Negative Regulator ◽  
Ras Signaling ◽  
Nerve Sheath Tumor ◽  
Cutaneous Manifestations ◽  
Nerve Sheath ◽  
Café Au Lait Spots ◽  
Nf1 Gene

Abstract Neurofibromatosis type 1 (NF1) is an autosomal dominant condition affecting 1 in 3,500 people resulting from an NF1 gene mutation that encodes the nonfunctional protein neurofibromin mutant. Neurofibromin is a negative regulator of RAS signaling involved in cell survival and proliferation. NF1 typically presents at birth or in early childhood with multiple light brown (café au lait) spots and axillary freckling. With age, patients may develop scattered neurofibromas as well as additional neurological and malignant abnormalities. Additionally, the nonfunctional protein neurofibromin mutant may be involved in the pathogenesis of peripheral malignant nerve sheath tumors, which is a rare and life-threatening complication of NF1. While a disqualifying condition for military duty, it may not initially be clinically apparent until complications develop. Here, we present a case of malignant peripheral sheath in an U.S. Army African American reservist with NF1 in whom cutaneous manifestations of NF1 such as café au lait spots and axillary freckling were not identified on the initial military entrance processing examination.

scholarly journals In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

2015 ◽  
Vol 112 (29) ◽  
pp. 9034-9039 ◽  
Author(s):  
Jennifer Allouche ◽  
Nathalia Bellon ◽  
Manoubia Saidani ◽  
Laure Stanchina-Chatrousse ◽  
Yolande Masson ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Signaling Pathways ◽  
Human Embryonic Stem Cells ◽  
Neurofibromatosis Type 1 ◽  
Molecular Mechanisms ◽  
Embryonic Stem ◽  
Neurofibromatosis Type

“Café-au-lait” macules (CALMs) and overall skin hyperpigmentation are early hallmarks of neurofibromatosis type 1 (NF1). One of the most frequent monogenic diseases, NF1 has subsequently been characterized with numerous benign Schwann cell-derived tumors. It is well established that neurofibromin, the NF1 gene product, is an antioncogene that down-regulates the RAS oncogene. In contrast, the molecular mechanisms associated with alteration of skin pigmentation have remained elusive. We have reassessed this issue by differentiating human embryonic stem cells into melanocytes. In the present study, we demonstrate that NF1 melanocytes reproduce the hyperpigmentation phenotype in vitro, and further characterize the link between loss of heterozygosity and the typical CALMs that appear over the general hyperpigmentation. Molecular mechanisms associated with these pathological phenotypes correlate with an increased activity of cAMP-mediated PKA and ERK1/2 signaling pathways, leading to overexpression of the transcription factor MITF and of the melanogenic enzymes tyrosinase and dopachrome tautomerase, all major players in melanogenesis. Finally, the hyperpigmentation phenotype can be rescued using specific inhibitors of these signaling pathways. These results open avenues for deciphering the pathological mechanisms involved in pigmentation diseases, and provide a robust assay for the development of new strategies for treating these diseases.

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