title: In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells.
abstract: "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.
authors.affiliation: INSERM U-861, Institut des cellules Souches pour le Traitement et l'Etude des Maladies monogéniques (I-Stem), Association Française contre les Myopathies (AFM), 91030 Evry Cedex, France; Université d'Evry Val d'Essonne (UEVE) U-861, I-Stem, AFM, 91030 Evry Cedex, France;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Allouche
authors.affiliation: Department of Dermatology, Reference Center for Dermatologic Diseases, Paris Descartes-Sorbonne Paris Cité University, 75015 Paris, France; Centre d'Etude des Cellules Souches (CECS), I-Stem, AFM, 91030 Evry Cedex, France; Instiute Imagine, Necker-Enfants Malades Hospital, 75015 Paris, France;
authors.forename: Nathalia
authors.initials: N
authors.lastname: Bellon
authors.affiliation: Centre d'Etude des Cellules Souches (CECS), I-Stem, AFM, 91030 Evry Cedex, France;
authors.forename: Manoubia
authors.initials: M
authors.lastname: Saidani
authors.affiliation: Centre d'Etude des Cellules Souches (CECS), I-Stem, AFM, 91030 Evry Cedex, France;
authors.forename: Laure
authors.initials: L
authors.lastname: Stanchina-Chatrousse
authors.affiliation: Centre d'Etude des Cellules Souches (CECS), I-Stem, AFM, 91030 Evry Cedex, France;
authors.forename: Yolande
authors.initials: Y
authors.lastname: Masson
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, F-75248 Paris, France; Structure and Membrane Compartments, CNRS UMR 144, F-75248 Paris, France;
authors.forename: Anand
authors.initials: A
authors.lastname: Patwardhan
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, F-75248 Paris, France; Structure and Membrane Compartments, CNRS UMR 144, F-75248 Paris, France;
authors.forename: Floriane
authors.initials: F
authors.lastname: Gilles-Marsens
authors.affiliation: Institut Curie, Paris Sciences et Lettres Research University, F-75248 Paris, France; Structure and Membrane Compartments, CNRS UMR 144, F-75248 Paris, France; Cell and Tissue Imaging Facility, CNRS UMR 144, F-75248 Paris, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Delevoye
authors.affiliation: Centre d'Etude des Cellules Souches (CECS), I-Stem, AFM, 91030 Evry Cedex, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Domingues
authors.affiliation: Centre d'Etude des Cellules Souches (CECS), I-Stem, AFM, 91030 Evry Cedex, France;
authors.forename: Xavier
authors.initials: X
authors.lastname: Nissan
authors.affiliation: INSERM U-861, Institut des cellules Souches pour le Traitement et l'Etude des Maladies monogéniques (I-Stem), Association Française contre les Myopathies (AFM), 91030 Evry Cedex, France; Université d'Evry Val d'Essonne (UEVE) U-861, I-Stem, AFM, 91030 Evry Cedex, France;
authors.forename: Cécile
authors.initials: C
authors.lastname: Martinat
authors.affiliation: INSERM U-861, Institut des cellules Souches pour le Traitement et l'Etude des Maladies monogéniques (I-Stem), Association Française contre les Myopathies (AFM), 91030 Evry Cedex, France; Université d'Evry Val d'Essonne (UEVE) U-861, I-Stem, AFM, 91030 Evry Cedex, France;
authors.forename: Gilles
authors.initials: G
authors.lastname: Lemaitre
authors.affiliation: INSERM U-861, Institut des cellules Souches pour le Traitement et l'Etude des Maladies monogéniques (I-Stem), Association Française contre les Myopathies (AFM), 91030 Evry Cedex, France; Université d'Evry Val d'Essonne (UEVE) U-861, I-Stem, AFM, 91030 Evry Cedex, France;
authors.forename: Marc
authors.initials: M
authors.lastname: Peschanski
authors.affiliation: INSERM U-861, Institut des cellules Souches pour le Traitement et l'Etude des Maladies monogéniques (I-Stem), Association Française contre les Myopathies (AFM), 91030 Evry Cedex, France; Université d'Evry Val d'Essonne (UEVE) U-861, I-Stem, AFM, 91030 Evry Cedex, France; cbaldeschi@istem.fr.
authors.forename: Christine
authors.initials: C
authors.lastname: Baldeschi
mesh_terms: D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D017495:Hyperpigmentation / Q000473:pathology*; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000473:pathology*; D025542:Neurofibromin 1 / Q000235:genetics; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D008543:Melanins; D025542:Neurofibromin 1; D034741:RNA, Small Interfering; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: disease modeling; embryonic stem cells; hyperpigmentation; melanocytes; neurofibromatosis type 1