The settlement of melanoblast and the generation of pigment
After dorsolaterally migration, the melanoblast finds its destinations; and settled down surrounded by epithelial cells. What attracts melanoblast to settle in these particular regions in molecular level?
The role of the apical ectodermal ridge and of fibroblast growth factors FGF-2 and FGF-4 and of the insulin-like growth factor I (IGF-I) in the control of the migration of epidermal melanoblast into wing buds was investigated using quail–chicken chimeras. As the results, both the apical ectodermal ridge and the growth factors invariably caused the migration of epidermal melanoblasts towards them. Furthermore, FGF-2 and IGF-I and to a lesser extent FGF-4 play a decisive role in directing the migration of epidermal melanoblasts within chicken wing buds and are likely to be involved in the molecular cascade by means of which the apical ectodermal ridge controls the migration of epidermal melanoblasts. Although IGF-1 acts as upstream regulator of FGFs; FGFs have been shown to promote survival and proliferation of melanoblasts, further study has shown that the proliferation of melanoblasts can also be promoted by IGF-I, independent with FGFs (Schofer, et al., 2001).
Reaching to the destination is not sufficient for melanoblast settlement. As a kind of steam cell, melanoblast needs a population of cells (known as a “niche”) surrounding it to keep its capacity to self-renew and generate differentiated progeny (Nishimura, et al., 2002). At specific cutaneous sites, epithelial cells use Foxn1 (a transcription factor) to recruit melanocytes and induce their own pigmentation. Foxn1 thus defines a distinct cell population that ultimately controls the targeting of pigment in the skin (Weiner, et al., 2007).
After settlement, the melanoblast will start to exert its role, differentiated into melanocyte and generate pigmentation.
Mammals develop most of their coloration through a system comprised of two types of cells (reviewed by Slominski et al., 2004), referred to here as pigment donors and recipients. The pigment donors are melanocytes, which synthesize melanin in distinct organelles called melanosomes. The pigment recipients are epithelial cells, which acquire and hold most cutaneous melanin. As the system forms, each melanocyte extends dendrites and contacts multiple epithelial cells, creating a ‘‘pigmentary unit.’’ Melanosomes are then transported along the dendrites and into the epithelial cells, which may internalize the melanosomes via phagocytosis (Weiner, et al., 2007).
But the relationship between the donor melanocytes and the recipient epithelial cells are not changeless. Some differentiated melanocytes can return to the “niche” and become stem-cell again (Nishimura, et al., 2002).
Studies of pigment generation in melanocytes always focus on the function of the three transcription factors MITF, PAX3, and SOX10. The pathways of these genes interact to regulate crucial aspects of melanocyte development and function. Microphthalmia-associated Transcription Factor (MITF) has been termed the “melanocyte master regulator”, because it plays such a central role in melanocyte development and function. It is required for melanocyte differentiation and survival, activates transcription of melanogenic enzymes and melanogenic proteins, and is associated with melanoma progression. MITF also governs numerous other cellular functions in the melanocyte, including environmental response, cell survival, cell motility, and cell cycle progression. MITF itself undergoes complex post-transcriptional regulation, including phosphorylation, sumoylation, ubiquitination, and caspase cleavage. Paired box gene 3 (PAX3) has a broader expression pattern than MITF, regulating neural tube closure, early development of myoblast and neural crest lineages, and the formation of nervous, muscular, cardiovascular and melanocyte systems. PAX3 regulation of early neural crest development appears to maintain neural crest stem cell properties via inhibition of apoptosis, and PAX3 has been proposed to inhibit apoptosis in melanoma. In melanocytes, PAX3 activates transcription of MITF and plays a crucial role in maintaining melanocyte stem cells. SRY-box containing gene 10 (SOX10) regulates specification of neural crest-derived melanocytes, neurons, and glia. SOX10 strongly activates MITF and regulates expression of melanogenic enzymes. Upstream regulation of SOX10, as well as additional downstream targets, interacting factors, and posttranslational modifications are only beginning to be ascertained. In summary, MITF, PAX3, and SOX10 serve to illustrate that the extensive data currently known on cellular processes governing melanocyte biology will provide an ideal foundation for future systems biology analyses in these cells (reviewed by Baxter et al., 2009).
Schofer, C., Frei, K., Weipoltshammer, K., and Wachtler, F. The apical ectodermal ridge, fibroblast growth factors (FGF-2 and FGF- 4) and insulin-like growth factor I (IGF-I) control the migration of epidermal melanoblasts in chicken wing buds. Anat. Embryol. (Berl.) 2001. 203, 137–146.
Emi K. Nishimura, Siobhan A. Jordan, Hideo Oshima, Hisahiro Yoshida, Masatake Osawa, Mariko Moriyama, Ian J. Jackson§, Yann Barrandonk, Yoshiki Miyachi, Shin-Ichi Nishikawa. Dominant role of the niche in melanocyte stem-cell fate determination. Nature, 2002, Vol 416, 25 April. 854-860.
Lorin Weiner, Rong Han, Bianca M. Scicchitano, Jian Li, Kiyotaka Hasegawa, Maddalena Grossi, David Lee, Janice L. Brissette. Dedicated Epithelial Recipient Cells Determine Pigmentation Patterns. Cell. 2007. 07. 024.
Slominski, A., Tobin, D.J., Shibahara, S., and Wortsman, J. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol. Rev. 2004. 84, 1155–1228.
Laura L Baxter, Stacie K Loftus, William J Pavan. Networks and pathways in pigmentation, health, and disease. Wiley Interdiscip Rev Syst Biol Med. 2009 November 1; 1(3): 359–371.