Melanocyte | EPFL Graph Search

Melanocytes are melanin-producing neural crest-derived cells located in the bottom layer (the stratum basale) of the skin's epidermis, the middle layer of the eye (the uvea), the inner ear, vaginal epithelium, meninges, bones, and heart. Melanin is a dark pigment primarily responsible for skin color. Once synthesized, melanin is contained in special organelles called melanosomes which can be transported to nearby keratinocytes to induce pigmentation. Thus darker skin tones have more melanosomes present than lighter skin tones. Functionally, melanin serves as protection against UV radiation. Melanocytes also have a role in the immune system. Function Through a process called melanogenesis, melanocytes produce melanin, which is a pigment found in the skin, eyes, hair, nasal cavity, and inner ear. This melanogenesis leads to a long-lasting pigmentation, which is in contrast to the pigmentation that originates from oxidation of already-existing melanin. There are both basal

Analysis of the Pigment Cell Specific Gene MART-1/Melan-A/mlana

Iraz Toprak Aydin

Pigmentation is a complex process that provides many diverse benefits for the organism. Pigment production takes place in the pigment cell lineage in dedicated organelles called melanosomes. Several proteins are specifically recruited to melanosomes for this purpose, and many of them are involved in melanin synthesis. MART-1 is one of the melanosomal proteins. It has been widely studied as an agent for immunotherapy against malignant melanoma but very little is known about the gene and its function. Here, I used different approaches in order to understand the biology of this pigment cell specific gene. First, I analyzed transcriptional regulation of the mouse MART-1 gene. I found that the shortest promoter region (0.6kb) alone is not sufficient to drive the expected MART-1 expression in vivo, even though it was able to express a luciferase reporter in vitro, in transfected cells. The largest promoter region (6.0kb) was able to produce expression of a LacZ reporter gene in the RPE layer starting from the early stages of embryogenesis. However it failed to drive melanoblast-specific expression in embryos and, only after birth, reporter gene expression in melanocytes became visible, indicating that distal regulatory elements might be involved in melanocyte/melanoblastspecific MART-1 expression. In order to visualize the spatial and temporal expression pattern of MART-1, I developed a MART-1::LacZ BAC reporter mouse and showed that in mouse, MART-1 expression starts at around E11.5-12.5, and its expression is exclusive to melanocytes and RPE. To understand the function of MART-1, I developed a knockout mouse model. I have shown for the first time that MART-1 is directly involved in pigmentation and that its loss leads to coat color dilution. It has been reported that MART-1 might be involved in trafficking and processing of the melanosomal proteins Pmel17 and OA1. I analyzed the distribution of Pmel17 and OA1, as well as other melanosomal proteins in melanocyte lines derived from MART-1 knockout mice, however no mislocalizations were observed. Besides, in primary knockout melanocytes, the processing of Pmel17 was not affected. Nevertheless, electron microscopy studies revealed that MART-1 knockout mice had severe morphological defects in melanosomes of the hair follicle melanocytes. This indicated that the coat color dilution observed in MART-1 knockout mice might be due to the structural defects in the melanosomes, suggesting that MART-1 is required for melanosome biogenesis in the hair follicle.

EPFL2010

The Notch signaling pathway

Karine Schouwey

In animals, pigment cells are essential for coloration, as seen in feathers, fur, skin and eyes. In mammals, neural crest-derived melanocytes constitute the major population of pigment cells that is located mainly in the skin epidermis, as well as in hair follicles. A minor population of pigment cells originates from the optic cup and forms the retinal pigment epithelium (RPE), a cell monolayer lying between the neural retina and the choroid. In many cell types, the Notch signaling pathway regulates diverse biological processes such as cell fate decision, differentiation, stem cell maintenance or apoptosis. In my thesis project, the role of this pathway was investigated using Notch1, Notch2 and RBP-Jκ conditional knockout mice. Disruption of the Notch pathway by inactivation of Notch1 and Notch2, or RBP-Jκ in the melanocyte lineage using Tyr::Cre transgenic mice resulted in a gene dosage-dependent precocious hair graying, with the most pronounced effect seen in mice lacking both Notch1 and Notch2 in melanocytes. Histologically, this coat color dilution was explained by the progressive elimination of melanocytes and melanocyte stem cells, identified in skin or embryos by X-Gal staining (Dct::LacZ reporter mouse line) and immunofluorescence analyses. As in neural crest-derived melanocytes, members of the Notch signaling pathway are normally expressed in pigment cells of the RPE. The RPE-restricted deletion of RBP-Jκ using Tyrp1::Cre transgenic mice resulted in a microphthalmic eye phenotype and thus indicated a role of the Notch pathway in the development of the RPE. Further analyses demonstrated that misregulation of Notch signaling in RPE induced a reduction in the number of these pigment cells. In addition to these knockout studies, I have generated transgenic mouse lines that express the constitutively activated intracellular part of Notch (NotchIC) in melanocytes (Dct::NotchIC) and RPE cells (Tyrp1::NotchIC). Since these mice rescue the phenotypes observed in the conditional Notch receptor knockouts, they are instrumental to assess the implication of active Notch signaling in pigment cell development and tumorigenesis. Moreover, it might be determined whether constitutive activation of Notch can prevent physiological hair graying and loss of stem cells. In summary, my results underline the importance of fine-tuned Notch signaling for proper hair pigmentation and, more generally, for pigment cell development.

EPFL2009

Constitutive gray hair in Mice induced by Melanocyte-specific deletion of c-Myc

Marzia Armaro, Friedrich Beermann, Karine Schouwey

c-Myc is involved in the control of diverse cellular processes and implicated in the maintenance of different tissues including the neural crest. Here we report that c-Myc is particularly important for pigment cell development and homeostasis. Targeting c-Myc specifically in the melanocyte lineage using the floxed allele of c-Myc and Tyr::Cre transgenic mice results in a congenital gray hair phenotype. The gray coat color is associated with a reduced number of functional melanocytes in the hair bulb and melanocyte stem cells (MSCs) in the hair bulge. Importantly the gray phenotype does not progress with time suggesting that maintenance of the melanocyte through the hair cycle does not involve c-Myc function. In embryos, at E13.5, c-Myc-deficient melanocyte precursors are affected in proliferation in concordance with a reduction in numbers showing that c-Myc is required for proper melanocyte development. Interestingly, melanocytes from c-Myc deficient mice display elevated levels of the c-Myc paralog N-Myc. Double deletion of c-Myc and N-Myc results in nearly complete loss of the residual pigmentation, indicating that N-Myc is capable of compensating for c-Myc loss of function in melanocytes. © 2012 John Wiley & Sons A/S.

2012