Melanocyte fate in neural crest is triggered by Myb proteins through activation of c-kit

Academy of Sciences of the Czech Republic, Praha, Praha, Czech Republic
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.81). 12/2007; 64(22):2975-84. DOI: 10.1007/s00018-007-7330-5
Source: PubMed


The c-myb proto-oncogene and its oncogenic derivative v−myb
encode transcriptional regulators engaged in the commitment of hematopoietic cells. While the c-Myb protein is important for the formation and differentiation of various progenitors, the v−MybAMV
oncoprotein induces in chicks a progression and transformation of the single (monoblastic) cell lineage. Here we present the first evidence of cell fate-directing abilities of c-Myb and v−MybAMV
proteins in avian neural crest (NC), where both proteins determine melanocytogenesis. The increased concentration of c-Myb induces progression into dendritic melanocytes and differentiation. The v-myb oncogene converts essentially all NC cells into melanocytes and causes their transformation. Both Myb proteins activate in NC cells expression of the c-kit gene and stem cell factor c-Kit signaling – one of the essential pathways in melanocyte development. These observations suggest that the c-myb-c-kit pathway represents a common regulatory scheme for both hematopoietic and neural progenitors and establishes a novel experimental model for studies of melanocytogenesis and melanocyte transformation.

Download full-text


Available from: Vladimir Cermak, Jan 07, 2015
  • Source
    • "DNA constructs and retroviral stocks v-myb gene mutants (Fig. 1A) were constructed from the v-myb L3,4A leucine zipper mutant (Bartunek et al., 1997) by replacing the TAG stop codon with the fusion sequence encoding two hemagglutinin epitopes (HA) and the mouse estrogen receptor containing the G525R mutation (Karafiat et al., 2007). The v-Myb variant N118D, not recognizing MRE, was prepared earlier (Karafiat et al., 2007). 200 nM 4-hydroxytamoxifen (Sigma) was used for induction of v-myb-L3,4A- HAER proteins. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The neural crest (NC) is a transient dynamic structure of ectodermal origin, found in early vertebrate embryos. The multipotential NC cells migrate along well defined routes, differentiate to various cell types including melanocytes and participate in the formation of various permanent tissues. As there is only limited information about the molecular mechanisms controlling early events in melanocyte specification and development, we exploited the AMV v-Myb transcriptional regulator, which directs differentiation of in vitro chicken NC cells to the melanocyte lineage. This activity is strictly dependent on v-Myb specifically binding to the Myb recognition DNA element (MRE). The two tamoxifen-inducible v-Myb alleles were constructed one which recognizes the MRE and one which does not. These were activated in ex ovo NC cells, and the expression profiles of resulting cells were analyzed using Affymetrix microarrays and RT-PCR. These approaches revealed up-regulation of the BMP antagonist Gremlin 2 mRNA, and down-regulation of mRNAs encoding several epithelial genes including KRT19 as very early events following the activation of melanocyte differentiation by v-Myb. The enforced v-Myb expression in neural tubes of chicken embryos resulted in detectable presence of Gremlin 2 mRNA. However, expression of Gremlin 2 in NC cells did not promote formation of melanocytes suggesting that Gremlin 2 is not the master regulator of melanocytic differentiation.
    Gene 02/2014; 540(1). DOI:10.1016/j.gene.2014.02.031 · 2.14 Impact Factor
  • Source
    • "The present data suggest that cMyb helps activate Ets1 and then, they both help to initiate and maintain expression of Sox10. Later in development, cMyb functions to specify melanocyte fate by regulating c-kit (Karafiat et al., 2007), suggesting that cMyb plays multiple spatially and temporally distinct roles in the neural crest. Our NanoString data suggest that cMyb is involved in the regulation of neural and neural plate border genes Gbx2, Six1, Twist and Pax7 in the late gastrula embryo. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The transcription factor cMyb has well known functions in vertebrate hematopoiesis, but little was known about its distribution or function at early developmental stages. Here, we show that cMyb transcripts are present at the neural plate during gastrulation in chick embryos. cMyb expression then resolves to the cranial neural folds and is maintained in early migrating cranial neural crest cells during and after neurulation. Morpholino-mediated knock-down of cMyb reduces expression of Pax7 and Twist at the neural plate border, as well as reducing expression of neural crest specifier genes Snail2 and Sox10 and completely eliminating expression of Ets1. On the other hand, its loss results in abnormal maintenance of Zic1, but little or no effect on other neural crest specifier genes like FoxD3 or Sox9. These results place cMyb in a critical hierarchical position within the cranial neural crest cell gene regulatory network, likely directly inhibiting Zic1 and upstream of Ets1 and some, but not all, neural crest specifier genes.
    Mechanisms of development 02/2014; 132(1). DOI:10.1016/j.mod.2014.01.005 · 2.44 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.
    The Journal of clinical investigation 07/2009; 119(6):1420-8. DOI:10.1172/JCI39104 · 13.22 Impact Factor
Show more