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Schwann Cell Precursors from Nerve Innervation Are a Cellular Origin of Melanocytes in Skin

Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden.
Cell (Impact Factor: 33.12). 10/2009; 139(2):366-79. DOI: 10.1016/j.cell.2009.07.049
Source: PubMed

ABSTRACT Current opinion holds that pigment cells, melanocytes, are derived from neural crest cells produced at the dorsal neural tube and that migrate under the epidermis to populate all parts of the skin. Here, we identify growing nerves projecting throughout the body as a stem/progenitor niche containing Schwann cell precursors (SCPs) from which large numbers of skin melanocytes originate. SCPs arise as a result of lack of neuronal specification by Hmx1 homeobox gene function in the neural crest ventral migratory pathway. Schwann cell and melanocyte development share signaling molecules with both the glial and melanocyte cell fates intimately linked to nerve contact and regulated in an opposing manner by Neuregulin and soluble signals including insulin-like growth factor and platelet-derived growth factor. These results reveal SCPs as a cellular origin of melanocytes, and have broad implications on the molecular mechanisms regulating skin pigmentation during development, in health and pigmentation disorders.

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    • "They further show that Desert hedgehog Cre (Dhh-Cre) (Jaegle et al., 2003), another proposed SCP marker, does not label melanoblasts or future melanocytes in the mouse. Furthermore, the transplantation studies of Rawles (1940) (1947) and Mayer (1973) suggest that functional melanoblast populations, able to colonise graft and host tissue, are present in the dermis at E11 and in the dermis and epidermis at E12, overlapping the window in which Adameyko et al. suggest melanoblasts in the dorsolateral aspect become absent (Adameyko et al., 2009). Thus, whilst the common embryonic origin of melanocytes and glia, and the plasticity of the adult Schwann cell, are not in doubt, further work, using alternative approaches to Plp- CreERT2, is required to dissect the developmental timings and lineage relationships of melanoblasts and SCPs in the developing mouse embryo. "
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    ABSTRACT: Melanocyte development provides an excellent model for studying more complex developmental processes. Melanocytes have an apparently simple aetiology, differentiating from the neural crest and migrating through the developing embryo to specific locations within the skin and hair follicles, and to other sites in the body. The study of pigmentation mutations in the mouse provided the initial key to identifying the genes and proteins involved in melanocyte development. In addition, work on chicken has provided important embryological and molecular insights, whereas studies in zebrafish have allowed live imaging as well as genetic and transgenic approaches. This cross-species approach is powerful and, as we review here, has resulted in a detailed understanding of melanocyte development and differentiation, melanocyte stem cells and the role of the melanocyte lineage in diseases such as melanoma. © 2015. Published by The Company of Biologists Ltd.
    Development 02/2015; 142(4):620-632. DOI:10.1242/dev.106567 · 6.27 Impact Factor
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    • "The interest in the HMX1 transcription factor has surged with the discovery in 2008 that it was causing the oculo-auricular syndrome of Schorderet-Munier-Franceschetti [12]. In addition of being expressed in somatosensory organs [23], Hmx1 has been shown to retain a neuronal fate in migrating neural crest cells [24] and to modulate the adrenergic/cholinergic program of sympathic neurons [25]. It is also well expressed in sensory spinal and cranial ganglia [9]. "
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    ABSTRACT: HMX1 is a homeobox-containing transcription factor implicated in eye development and responsible for the oculo-auricular syndrome of Schorderet-Munier-Franceschetti. HMX1 is composed of two exons with three conserved domains in exon 2, a homeobox and two domains called SD1 and SD2. The function of the latter two domains remains unknown. During retinal development, HMX1 is expressed in a polarized manner and thus seems to play a role in the establishment of retinal polarity although its exact role and mode of action in eye development are unknown. Here, we demonstrated that HMX1 dimerized and that the SD1 and homeodomains are required for this function. In addition, we showed that proper nuclear localization requires the presence of the homeodomain. We also identified that EPHA6, a gene implicated in retinal axon guidance, is one of its targets in eye development and showed that a dimerized HMX1 is needed to inhibit EPHA6 expression.
    PLoS ONE 06/2014; 9(6):e100096. DOI:10.1371/journal.pone.0100096 · 3.23 Impact Factor
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    • "Furthermore, our data appear to highlight a novel link between the processes underlying the development and homeostasis of BLCs. It has been suggested that during development, the neural crest-derived Sox10+ Schwann cell precursors (SCPs) along peripheral nerves are directed to melanocyte fate by microphtalmia-associated transcription factor (MITF) [52]. Our investigation of BLCs in the developed limbus indicates as well, high activity of processes in the categories covering Neural Crest Cell Development and Neural Crest Cell Differentiation, entailing most noteworthy up-regulation of SOX10 and MITF. "
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    ABSTRACT: Corneal epithelium is maintained throughout life by well-orchestrated proliferation of limbal epithelial stem cells (LESCs), followed by migration and maturation centripetally towards the ocular surface. Disturbance of LESCs can potentially lead to a blinding condition, which can be reversed by reconstitution of a functional LESC pool. The current clinical procedures are effective to some degree, however, deeper knowledge of the molecular interplay within the limbal niche is necessary to achieve a fully satisfactory patient outcome. The present study was thus undertaken to carry out a comprehensive transcriptome analysis of four distinct human limbal compartments, including basal limbal crypts (BLCs), superficial limbal crypts (SLCs), cornea, and the supporting stroma, with the aid of laser capture microdissection and deep RNA sequencing. The tissue harvest pipeline was rigorously optimized so that the exposure to cold ischemia would be less than five minutes. The global gene ontology analysis confirmed existence of primitive cells in BLCs, migratory and activated cells in SLCs, and differentiated cells in cornea. Interestingly, many significantly upregulated genes in SLCs mapped to processes involved in regulation of vasculature, such as sFLT1. In contrast, BLCs exhibited many genes mapping to neurogenic processes and processes related to cell development. The primitive nature of BLCs was, furthermore, confirmed by the KEGG pathway analysis, and some potential regulators of LESCs were revealed, such as Lrig1 and SOX9. The analysis also yielded comprehensive lists of uniquely expressed genes in both BLCs and cornea, which may be useful to identify possible biomarkers. In conclusion, the current investigation provides new insight into the relationship between distinct cell populations within the limbal niche, identifies candidates to be verified for novel biological functions, and yields a wealth of information for prospective data mining.
    PLoS ONE 11/2013; 8(5):e64244. DOI:10.1371/journal.pone.0064244 · 3.23 Impact Factor
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