Proliferation Of Melanoblasts Research Articles

The Ednrb–Aim2–AKT axis regulates neural crest-derived melanoblast proliferation during early development

ABSTRACT Ednrb is specifically required to develop neural crest (NC) stem cell-derived lineages. However, it is still unknown why Ednrb signaling is only needed for the early development of melanoblasts in the skin and eye. We show that Ednrb is required for the proliferation of melanoblasts during early mouse development. To understand the mechanism of melanoblast proliferation, we found that the gene absent in melanoma 2 (Aim2) is upregulated in Ednrb-deficient NC cells by RNA-sequencing analysis. Consequently, the knockdown or knockout of Aim2 partially rescued the proliferation of Ednrb-deficient melanoblasts. Conversely, the overexpression of Aim2 in melanoblasts suppressed their proliferation. We further show that Ednrb signaling could act through the microRNA miR-196b to block the suppression of melanoblast proliferation by Aim2 in primary NC cell cultures. These results reveal the Ednrb–Aim2–AKT axis in regulating melanocyte development and suggest that Ednrb signaling functions as a negative regulator of Aim2, which inhibits the proliferation of melanoblasts in early development. These findings uncover a previously unreported role for Aim2 outside the inflammasome, showing that it is a significant regulator controlling NC stem cell-derived lineage development.

Efficient generation of cloned cats with altered coat colour by editing of the KIT gene

Coat colour largely determines the market demand for several cat breeds. The KIT proto-oncogene (KIT) gene is a key gene controlling melanoblast differentiation and melanogenesis. KIT mutations usually cause varied changes in coat colour in mammalian species. In this study, we used a pair of single-guide RNAs (sgRNAs) to delete exon 17 of KIT in somatic cells isolated from two different Chinese Li Hua feline foetuses. Edited cells were used as donor nuclei for somatic cell nuclear transfer (SCNT) to generate cloned embryos presenting an average cleavage rate exceeding 85%, and an average blastocyst formation rate exceeding 9.5%. 131 cloned embryos were transplanted into four surrogates, and all surrogates carried their pregnancies to term, and delivered 4.58% (6/131) alive cloned kittens, with 1.53% (2/131) being KIT-edited heterozygotes (KITD17/+). The KITD17/+ cats presented an obvious darkness reduction in the mackerel tabby coat. Immunohistochemical analysis (IHC) of skin tissues indicated impaired proliferation and differentiation of melanoblasts caused by the lack of exon17 in feline KIT. To our knowledge, this is the first report on coat colour modification of cats through gene editing. The findings could facilitate further understanding of the regulatory role of KIT on feline coat colour and provide a basis for the breeding of cats with commercially desired coat colour.

Enhanced quality of hESC-derived melanocytes through modified concentration of endothelin-1.

The study investigated the effectiveness of EDN1 and EDN3 cytokines in the differentiation of melanocytes from hESCs. The findings showed that 100 nM EDN1 was more effective in promoting hESC to CD117+/TYR+ melanoblasts compared to 100 nM EDN3. Additionally, maintaining melanoblasts is beneficial for preserving the ability to proliferate. The study found that 10 nM EDN1 helped maintain the proliferation of melanoblasts without over maturing them into melanocytes in the late stage of differentiation. Thus, using 100 nM EDN1 in the initial stage and 10 nM EDN1 in the late stage proved to be an efficient and cost-effective method for obtaining hESC-derived melanocytes. The preliminary results suggest that EDN1 promotes melanoblast formation during the initial differentiation stage through its binding to both the EDNRB receptor and EDNRA receptor. This study provides a valuable tool for studying the development of human melanocytes and modelling the biology of disease.

Giant congenital melanocytic nevi (garment variety): a case report

Giant congenital melanocytic nevi (GCMN) are large brown-to-black skin lesions caused due to genetic mutations which lead to defective proliferation, differentiation and migration of melanoblasts which are precursor cells of melanocytes. There is a mutation in the NRAS gene causing abnormal proliferation of embryonic melanoblasts. Congenital melanocytic nevus is primarily a clinical diagnosis. The malignant melanoma and neurocutaneous melanosis are the two major complications associated with GCMN. The risk of transformation of GCMN to malignant melanoma varies between 0 and 3.8%. About 1% of live births presents with a CMN. The incidence of GCMN is estimated at less than 1: 20,000 newborns. The variety ‘garment-like’ of GCMN is even scarcer, 1: 5,00,000. GCMN has got major psychosocial impact on the patient and his family due to its unsightly appearance. Treatment includes surgical and non-surgical procedures, psychological intervention and clinical follow-up, with special attention to changes in color, texture on the surface of the lesion. We presented a case of 1-day-old female neonate born with GCMN in our hospital.

The additive efficacy of therapeutic low-intensity pulsed ultrasound in the treatment of vitiligo: A randomized, left-right comparison clinical trial.

Repigmentation of vitiligo relies on the proliferation and migration of melanoblasts from hair follicles to the epidermis to replenish epidermal melanin. Our previous study has demonstrated low-intensity pulsed ultrasound (LIPUS) can stimulate melanoblast migration in vitro. We sought to evaluate the potential additive efficacy and safety of LIPUS for repigmentation of vitiligo. Twenty-seven adult patients with stable generalized vitiligo on the face or trunk were recruited in this randomized, open, left-right comparison study. In each patient, two symmetric lesional sites were randomly selected; one was assigned as the target lesion, which was treated with add-on LIPUS twice weekly for 24 weeks, and the other as the control lesion, which was administrated with sham sonification. The primary outcome was the difference of repigmentation degree between the target and control lesions at week 24, based on the 7-point physician global assessment score. At the end of study, 23 patients with vitiligo on the face (n = 10) or trunk (n = 13) completed the 24-week treatment course. Enhanced repigmentation for vitiligo receiving LIPUS as compared to sham sonification was observed in 38.5% (5/13) of the patients with truncal vitiligo, but none of those with facial vitiligo. Truncal vitiligo (P = .046) and higher intensity of LIPUS administered (P = .01) were statistically significantly associated with the effectiveness of additive LIPUS treatment. The LIPUS treatment was well-tolerated without remarkable adverse effects. This pilot study showed that LIPUS could provide therapeutic benefits and could be considered as a treatment adjunct for truncal vitiligo.

FGF2 Stimulates the Growth and Improves the Melanocytic Commitment of Trunk Neural Crest Cells.

Neural crest cells (NCCs) comprise a population of multipotent progenitors and stem cells at the origin of the peripheral nervous system (PNS) and melanocytes of skin, which are profoundly influenced by microenvironmental factors, among which is basic fibroblast growth factor 2 (FGF2). In this work, we further investigated the role of this growth factor in quail trunk NC morphogenesis and demonstrated its huge effect in NCC growth mainly by stimulating cell proliferation but also reducing cell death, despite that NCC migration from the neural tube explant was not affected. Moreover, following FGF2 treatment, reduced expression of the early NC markers Sox10 and FoxD3 and improved proliferation of HNK1-positive NCC were observed. Since these markers are involved in the regulation of glial and melanocytic fate of NC, the effect of FGF2 on NCC differentiation was investigated. Therefore, in the presence of FGF2, increased proportions of NCCs positives to the melanoblast marker Mitf as well as NCCs double stained to Mitf and BrdU were recorded. In addition, treatment with FGF2, followed by differentiation medium, resulted in increased expression of melanin and improved proportion of melanin-pigmented melanocytes without alteration in the glial marker Schwann myelin protein (SMP). Taken together, these data further reveal the important role of FGF2 in NCC proliferation, survival, and differentiation, particularly in melanocyte development. This is the first demonstration of FGF2 effects in melanocyte commitment of NC and in the proliferation of Mitf-positive melanoblasts. Elucidating the differentiation process of embryonic NCCs brings us a step closer to understanding the development of the PNS and then undertaking the search for advanced technologies to prevent, or treat, injuries caused by NC-related disorders, also known as neurocristopathies.

Melanoblasts but not melanocytes decrease in number in human epidermis of idiopathic guttate hypomelanosis

Idiopathic guttate hypomelanosis (IGH) is a common disease that appears mainly in trunk, arms, and legs. IGH is a benign leukoderma characterized by multiple, hypo- or depigmented discrete macules. Although melanocytes have been reported to decrease in number in the IGH macules, changes in melanoblast number are not known. Moreover, satisfactory therapies for this disease have not been established. In this study, we investigated the presence of melanoblasts in the IGH macules, and tried to treat the IGH macules by mini-punch grafting using a machine (mMG) in combination with narrow-band ultraviolet B (NB-UVB) therapy. Mini-punch biopsies of the lesional skin of five patients (11–72-year-old men and woman) were fixed and processed to dopa and combined dopa-premelanin reactions to detect melanocytes and melanoblasts. Although similar melanocyte density was observed in the lesional epidermis compared with the normal epidermis, melanoblast density was dramatically decreased. Moreover, epidermal melanin accumulation was greatly reduced in the lesional skin. For the treatment of the IGH macules, numerous mini-punch biopsies were removed from both recipient lesional skin and donor normal scalp skin, and then the donor biopsies were placed into the holes of the lesional skin. After 1 week, we started to expose NB-UVB to the lesional skin and continued the exposures. Excellent color-matched repigmentation was soon obtained. These results suggest that melanoblast proliferation and/or differentiation in addition to the melanosome transfer are defected in IGH, and the mMG and NB-UVB can support the excellent color-matched repigmentation.

Overexpression of Porcine Kit Gene in Transgenic Mice Does not Affect Melanogenesis

The Kit gene is proto-oncogene, encoded stem cell factor and involved in melanocyte development. Also, Kit is expressed in epidermis and proliferation of melanoblasts which occur to pigmentation in skin, eyes and other tissues. Here we established porcine Kit genes overexpressed transgenic mice. The role of Kit gene was regulation in melanogensis remains unclear in porcine. Therefore, present study aims to ectopic expression porcine Kit gene in pigmentation of skin tissues. Our results showed that no effect on melanogenesis in ectopic Kit gene overexpressed transgenic mice. Further studies on Kit gene will provide insight into other specific roles in porcine and mice species.

Progressive Cribriform and Zosteriform Hyperpigmentation along with Vitiligo

Background: Progressive cribriform and zosteriform hyperpigmentation (PCZH) is a disorder of pigmentation. Although several cases of PCZH have been reported, cases that associated with vitiligo have not been published in the past. Aim: We report the case to reveal the interesting mosaicism reflecting on the skin. Case Presentation: This case presents a phenomenon of the coexistence of hyperpigmentation and depigmentation arranged in unilateral and symmetric distribution in one patient. Conclusion: The aetiology of the pigmental disorders is still unknown. The linear nature of the pigmented bands probably reflects the clonal migration and proliferation of embryonic melanoblasts, so somatic mosaicism that develops during embryogenesis appears to be the underlying aetiology, which is leading to proliferation and migration of two mixed populations of melanocytes with different potential for pigment production.

Sox10 regulates skin melanocyte proliferation by activating the DNA replication licensing factor MCM5

BackgroundThe control of cell proliferation is a fundamental aspect of tissue formation in development and regeneration. A cell type that illustrates this point particularly well is the neural crest-derived melanocyte, the pigment cell of vertebrates, as melanocytes can be followed easily during development and their pigment is directly visible in the integument of the adult. In mammals, melanocytes undergo physiological cycles of loss and proliferative regeneration during the hair cycle, and their proliferation is also critical during wound healing, repigmentation of depigmented lesions, and in melanoma formation and progression. Hence, a thorough analysis of the molecular parameters controlling melanocyte proliferation is crucial for our understanding of the physiology of this cell type both in health and disease. ObjectiveSOX10 is a critical regulator in melanocytes and melanoma cells, but its specific role in their proliferation is far from clear. In this study we analyze the role of SOX10 in regulating mammalian melanocyte proliferation in a mouse model. MethodsThe role of SOX10 in melanoblast proliferation was analyzed in Sox10/+ mice by co-staining for melanocyte-specific markers and cell proliferation. In vitro, the role of SOX10 was studied by manipulating its levels using RNAi and analyzing the effects on DNA synthesis and cell growth and on gene expression at the RNA and protein levels. ResultsReduction of Sox10 gene dose led to a reduction in the number of melanoblasts. Knockdown of Sox10 in melanocytes led to inhibition of cell proliferation and a decrease in the expression of the minichromosome maintenance complex component 5 (MCM5). In fact, SOX10 directly activated MCM5 transcription by binding to conserved SOX10 consensus DNA sequences in the MCM5 promoter. Furthermore, the defect in cell proliferation could be rescued partially by overexpression of MCM5 in Sox10 knockdown melanocytes. ConclusionThe results suggest that the SOX10-MCM5 axis plays an important role in controlling melanocyte proliferation. Our findings provide novel insights into the regulatory mechanisms of melanocyte proliferation and may have implications for our understanding of the roles of SOX10 and MCM5 in abnormal melanocyte proliferation disorders such as cutaneous melanoma.

Human fibroblasts treated with hydrogen peroxide stimulate human melanoblast proliferation and melanocyte differentiation, but inhibit melanocyte proliferation in serum-free co-culture system

BackgroundOxidative stress caused by hydrogen peroxide (H2O2) elicits harmful effects on human melanocytes such as DNA damage and cell death. On the contrary, H2O2 is known to possess beneficial effects on melanocytes. However, mechanisms of the beneficial effects of H2O2 on melanocytes have not been fully understood, especially the indirect effects on melanocyte proliferation and differentiation from cells constituting surrounding tissue environment such as fibroblasts. ObjectiveThe aim of this study was to clarify whether H2O2-treated human fibroblasts affect the proliferation and differentiation of human melanocytes using serum-free co-culture system. MethodsEpidermal melanoblasts and melanocytes were co-cultured with H2O2-treated or control fibroblasts in serum-free culture media. The effects of H2O2-treated fibroblasts were detected by changes in the proliferation and differentiation of melanoblasts/melanocytes. ResultsH2O2-treated fibroblasts stimulated the proliferation of melanoblasts and the differentiation, melanogenesis, and dendritogenesis of melanocytes, but inhibited the proliferation of melanocytes. In the melanocytes co-cultured with H2O2-treated fibroblasts, the expression of tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and KIT was increased, whereas TYRP2 and microphthalmia-associated transcription factor showed no change. ConclusionThese results suggest that H2O2-treated fibroblasts can produce and release some mitogenic and melanogenic factors toward melanoblasts in addition to some proliferation-inhibiting factors toward melanocytes. The stimulation of melanocyte differentiation seems to be performed through the upregulation of TYR, TYRP1, and KIT.

The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma.

ABSTRACTThe cell's repertoire of transfer RNAs (tRNAs) has been linked to cancer. Recently, the level of the initiator methionine tRNA (tRNAiMet) in stromal fibroblasts has been shown to influence extracellular matrix (ECM) secretion to drive tumour growth and angiogenesis. Here we show that increased tRNAiMet within cancer cells does not influence tumour growth, but drives cell migration and invasion via a mechanism that is independent from ECM synthesis and dependent on α5β1 integrin and levels of the translation initiation ternary complex. In vivo and ex vivo migration (but not proliferation) of melanoblasts is significantly enhanced in transgenic mice which express additional copies of the tRNAiMet gene. We show that increased tRNAiMet in melanoma drives migratory, invasive behaviour and metastatic potential without affecting cell proliferation and primary tumour growth, and that expression of RNA polymerase III-associated genes (which drive tRNA expression) are elevated in metastases by comparison with primary tumours. Thus, specific alterations to the cancer cell tRNA repertoire drive a migration/invasion programme that may lead to metastasis.

Platelet-derived growth factor regulates the proliferation and differentiation of human melanocytes in a differentiation-stage-specific manner

BackgroundAlthough many kinds of keratinocyte-derived factors are known to regulate the proliferation and differentiation of human melanocytes, it is not well defined whether dermis-derived factors work in a similar way. ObjectiveThe aim of this study is to clarify whether dermal factors are involved in regulating the proliferation and differentiation of human melanocytes. MethodsHuman epidermal melanoblasts were cultured serially in a serum-free growth medium. Platelet-derived growth factor-BB (PDGF-BB) was supplemented to the medium, and the effects on the proliferation of melanoblasts/melanocytes and the differentiation of melanocytes were studied. ResultsPDGF-BB stimulated the proliferation of melanoblasts cultured in melanoblast-proliferation medium, but inhibited the proliferation of melanocytes cultured in melanocyte-proliferation medium. By contrast, PDGF-BB stimulated the differentiation, dendritogenesis, and melanogenesis of melanocytes through the stimulation of tyrosinase activity and the expressions of tyrosinase and tyrosinase-related protein-1. ConclusionThese results suggest that PDGF-BB regulates the proliferation and differentiation of human melanocytes in a differentiation-stage-specific manner. PDGF-BB seems to be one of the dermal factors that regulate the proliferation and differentiation of human melanocytes.

Microphthalmia-associated transcription factor/T-box factor-2 axis acts through Cyclin D1 to regulate melanocyte proliferation.

Control of cell proliferation is critical for accurate cell differentiation and tissue formation, during development and regeneration. Here, we have analysed the role of microphthalmia-associated transcription factor MITF and its direct target, T-box factor TBX2, in regulating proliferation of mammalian neural crest-derived melanocytes. Immunohistochemistry was used to examine spatial and temporal expression of TBX2 in melanocytes in vivo. RNAi and cell proliferation analysis were used to investigate functional roles of TBX2. Furthermore, quantitative RT-PCR, western blot analysis and flow cytometry were used to further scrutinize molecular mechanisms underlying TBX2-dependent cell proliferation. TBX2 was found to be co-expressed with MITF in melanocytes of mouse hair follicles. Specific Tbx2 knockdown in primary neural crest cells led to inhibition MITF-positive melanoblast proliferation. Tbx2 knockdown in melan-a cells led to reduction in Cyclin D1 expression and G1-phase cell cycle arrest. TBX2 directly activated Ccnd1 transcription by binding to a specific sequence in the Ccnd1 promoter, and the defect in cell proliferation could be rescued partially by overexpression of Cyclin D1 in Tbx2 knockdown melanocytes. Results suggest that the Mitf-Tbx2-Cyclin D1 pathway played an important role in regulation of melanocyte proliferation, and provided novel insights into the complex physiology of melanocytes.

L-tyrosine induces melanocyte differentiation in novel pink-eyed dilution castaneus mouse mutant showing age-related pigmentation

BackgroundThe mouse pink-eyed dilution (oculocutaneous albinism II; p/Oca2p) locus is known to control tyrosinase activity, melanin content, and melanosome development in melanocytes. Pink-eyed dilution castaneus (pcas/Oca2p−cas) is a novel mutant allele on mouse chromosome 7 that arose spontaneously in Indonesian wild mice, Mus musculus castaneus. Mice homozygous for Oca2p−cas usually exhibit pink eyes and beige-colored coat on nonagouti C57BL/6 (B6) background. Recently, a novel spontaneous mutation occurred in the progeny between this mutant and B6 mice. The eyes of this novel mutant progressively become black from pink and the coat becomes dark gray from beige with aging. ObjectiveThe aim of this study is to clarify whatever differences exist in melanocyte proliferation and differentiation between the ordinary (pink-eyed) and novel (black-eyed) mutant using serum-free primary culture system. MethodsThe characteristics of melanocyte proliferation and differentiation were investigated by serum-free primary culture system using melanocyte-proliferation medium (MDMD). ResultsThe proliferation of melanoblasts in MDMD did not differ between the two mice. However, when the epidermal cell suspensions were cultured with MDMD supplemented with l-tyrosine (Tyr), the differentiation of black-eyed melanocytes was greatly induced in a concentration-dependent manner compared with pink-eyed melanocytes. Immunocytochemistry demonstrated that the expression of tyrosinase and tyrosinase-related protein-1 (Tyrp1) was greatly induced or stimulated both in pink-eyed and black-eyed melanocytes, whereas the expression of microphthalmia-associated transcription factor (Mitf) was stimulated only in black-eyed melanocytes. ConclusionThese results suggest that the age-related coat darkening in black-eyed mutant may be caused by the increased ability of melanocyte differentiation dependent on l-Tyr through the upregulation of tyrosinase, Tyrp1, and Mitf. This mutant mouse may be useful for animal model to clarify the mechanisms of age-related pigmentation in human skin, such as melasma and solar lentigines.

Piebaldismo-Moebius y exposición prenatal a misoprostol: reporte de un caso

Piebaldism is a rare congenital disease with prevalence of 1/100.000, characterized by patchy depigmentation of the skin and the presence of a white forelock. Its course is static and otherwise patients are healthy. It is inherited in an autosomal dominant pattern and is caused by mutations in the gene c-kit, a proto-oncogene involved in the migration, proliferation, differentiation and survival of melanoblasts. On the other hand, Moebius syndrome is a congenital palsy of the VII cranial nerve, which may be associated with involvement of other cranial nerves, or even of other systems. In the United States its frequency has been calculated from 0.002% to 0.0002% of total births. We report the case of a newborn girl with piebaldism and Moebius syndrome associated with prenatal exposure to misoprostol. A search was made about these anomalies and the association between prenatal exposure to misoprostol and congenital anomalies. Piebaldism is a rare genetic disorder. On the other hand, the cause of Moebius syndrome is heterogeneous and not well defined, and it has been associated with prenatal exposure to misoprostol. Our patient had simultaneously two diseases: one purely genetic and the other potentially teratogenic.

Possible Involvement of Keratinocyte Growth Factor in the Persistence of Hyperpigmentation in both Human Facial Solar Lentigines and Melasma.

Possible Involvement of Keratinocyte Growth Factor in the Persistence of Hyperpigmentation in both Human Facial Solar Lentigines and Melasma.

Identification and functional characterization of copy number variations in diverse chicken breeds.

BackgroundThe detection and functional characterization of genomic structural variations are important for understanding the landscape of genetic variation in the chicken. A recently recognized aspect of genomic structural variation, called copy number variation (CNV), is gaining interest in chicken genomic studies. The aim of the present study was to investigate the pattern and functional characterization of CNVs in five characteristic chicken breeds, which will be important for future studies associating phenotype with chicken genome architecture.ResultsUsing a commercial 385 K array-based comparative genomic hybridization (aCGH) genome array, we performed CNV discovery using 10 chicken samples from four local Chinese breeds and the French breed Houdan chicken. The female Anka broiler was used as a reference. A total of 281 copy number variation regions (CNVR) were identified, covering 12.8 Mb of polymorphic sequences or 1.07% of the entire chicken genome. The functional annotation of CNVRs indicated that these regions completely or partially overlapped with 231 genes and 1032 quantitative traits loci, suggesting these CNVs have important functions and might be promising resources for exploring differences among various breeds. In addition, we employed quantitative PCR (qPCR) to further validate several copy number variable genes, such as prolactin receptor, endothelin 3 (EDN3), suppressor of cytokine signaling 2, CD8a molecule, with important functions, and the results suggested that EDN3 might be a molecular marker for the selection of dark skin color in poultry production. Moreover, we also identified a new CNVR (chr24: 3484617–3512275), encoding the sortilin-related receptor gene, with copy number changes in only black-bone chicken.ConclusionsHere, we report a genome-wide analysis of the CNVs in five chicken breeds using aCGH. The association between EDN3 and melanoblast proliferation was further confirmed using qPCR. These results provide additional information for understanding genomic variation and related phenotypic characteristics.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-934) contains supplementary material, which is available to authorized users.

Stem cells in vitiligo: Current position and prospects

Skin is an easily accessible source of various sub population of stem cells including epidermal stem cells, hair follicle stem cells (HFSCs) and dermal mesenchymal stem cells. The outer root sheath (ORS) of the hair follicle is a rich source of a type of HFSCs called the melanocytes stem cells (MelSCs). These HFSCs have a vast, unexplored potential in the treatment of vitiligo as initial re-pigmentation often occurs around the hair follicles. Common therapeutic modalities such as tacrolimus, phototherapy and dermabrasion acts through MelSCs. Newer cellular techniques have explored the use of ORS hair follicle suspension in surgical treatment of vitiligo. Advancement in melanocyte and stem cell research has identified various cytokines, growth factors and regulators involved in proliferation and differentiation of melanoblasts, which can be used for autologous in situ melanocyte regeneration. In this review, we briefly discuss the current position and future prospects of stem cells in vitiligo.

Abstract C44: Targeting neuregulin1-ErbB3 signaling in wild-type BRAF/NRAS melanoma.

Abstract Melanoma is the deadliest form of skin cancer due to its highly metastatic nature and refractoriness to standard chemotherapies. At present, few therapy options exist for wild-type BRAF/NRAS (WT/WT) melanoma patients. We examined the role of the neuregulin (NRG1)-ErbB3 signaling pathway in WT/WT melanoma cells since it is emerging as an important player in melanocyte homeostasis and melanoma pathogenesis. NRG1 has been shown to promote melanoblast proliferation and survival. ErbB3 is elevated in malignant melanoma specimens and cell lines and its expression correlates with reduced patient survival. The purpose of this study was to determine the role of the NRG1-ErbB3 signaling pathway in WT/WT melanoma cells. We demonstrated that in a subgroup of WT/WT cell lines, expressing high level of ErbB3 and NRG1, neuregulin is able to activate ErbB3 in basal conditions. Knockdown of NRG1 in high NRG1-expressing cells led to reduction of cell viability. This effect was associated with a decrease in the phosphorylation of ErbB3 and ErbB2 receptors as well as downstream AKT and ERK1/2 signaling. All these effects were rescued by exogenous addition of NRG1. We obtained analogous effects targeting ErbB3 with either small interfering RNAs or with clinical grade ErbB3 monoclonal antibodies. In these WT/WT cell lines with high expression of NRG1, inhibition of ErbB2-ErbB3 dimerization with pertuzumab caused a decrease in AKT phosphorylation and cell growth, indicating that ErbB3 signaling is dependent on ErbB2. Synergistic effects on cell growth as well as on AKT and ERK1/2 signaling were observed targeting ErbB2 and ErbB3 combining both antibodies. Our study demonstrates that targeting ErbB3 and ErbB2 signaling in a cohort WT/WT melanoma cell lines leads to tumor growth reduction. We propose that NRG1 activation of ErbB3 signaling promotes progression in these tumors and that these findings may form the basis for the use of agents targeting the NRG1-ErbB3 axis as novel treatment strategies in a subset of malignant melanoma. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C44. Citation Format: Claudia Capparelli, Nadège Gaborit, Yosef Yarden, Andrew Aplin. Targeting neuregulin1-ErbB3 signaling in wild-type BRAF/NRAS melanoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C44.