Summary Melanocytes are pigment‐producing cells that reside in the skin, eyes, ears, heart, and central nervous system meninges of mammals. Schwann cells are glial cells, which closely associate with peripheral nerves, myelinating, and sheathing them. Melanocytes and Schwann cells both arise from the neural crest during development, and some melanocytes arise directly from Schwann cell precursors lining developing spinal nerves. In this review, we explore the connections between melanocytes and Schwann cells in development and transformation.
Mutations in neurofibromin (NF1) cause the dominant genetic disorder neurofibromatosis type 1. Neurofibromatosis is characterized by Schwann cell-based tumors and skin hyperpigmentation, resulting from both haploinsufficiency and loss of heterozygosity. The fact that some pigment cells (melanocytes) arise from Schwann cell precursors suggests that neurofibromin could be required during the common precursor stage. In this study, we found a missense mutation in neurofibromin in Dark skin 9 (Dsk9) mutant mice, revealing that Nf1 mutations cause skin hyperpigmentation in mice, as they do in humans. Using tissue-specific knockouts, we found that haploinsufficiency of neurofibromin in melanocytes via Mitf-cre is insufficient to cause darker skin, whereas haploinsufficiency in bipotential Schwann cell-melanoblast precursors via Plp1-creER is sufficient. These findings suggest that there is a narrow developmental window during which Nf1 haploinsufficiency acts on pigment cells. Using fate mapping, we discovered differences in the colonization of the dermis and epidermis by melanocytes that arise from Schwann cell precursors, an unexpected complexity of melanocyte development. As homozygous knockout of Nf1 via Mitf-cre is sufficient to cause darker skin, we conclude that reduced gene dosage can act by a mechanism different from complete gene loss, even when the end result of both is very similar.
When mutations in two different genes produce the same mutant phenotype, it suggests that the encoded proteins either interact with each other, or act in parallel to fulfill a similar purpose. Haploinsufficiency of Neurofibromin and over-expression of Endothelin 3 both cause increased numbers of melanocytes to populate the dermis during mouse development, and thus we are interested in how these two signaling pathways might intersect. Neurofibromin is mutated in the human genetic disease, neurofibromatosis type 1, which is characterized by the development of Schwann cell based tumors and skin hyper-pigmentation. Neurofibromin is a GTPase activating protein, while the Endothelin 3 ligand activates Endothelin receptor B, a G protein coupled receptor. In order to study the genetic interactions between endothelin and neurofibromin, we defined the deletion breakpoints of the classical Ednrb piebald lethal allele (Ednrbs-l) and crossed these mice to mice with a loss-of-function mutation in neurofibromin, Dark skin 9 (Dsk9). We found that Neurofibromin haploinsufficiency requires Endothelin receptor B to darken the tail dermis. In contrast, Neurofibromin haploinsufficiency increases the area of the coat that is pigmented in Endothelin receptor B null mice. We also found an oncogenic mutation in the G protein alpha subunit, GNAQ, which couples to Endothelin receptor B, in a uveal melanoma from a patient with neurofibromatosis type 1. Thus, this data suggests that there is a complex relationship between Neurofibromin and Endothelin receptor B.
Introduction: Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominantly inherited disorders affecting 1 in 3500 individuals. The NF1 gene encodes a protein called neurofibromin that has a Ras-GAP activity and acts as a tumor suppressor by negatively regulating Ras. Loss of neurofibromin has a pleiotropic effect affecting a number of cell types. We are interested in using the elegance and sensitivity of the pigmentary system to understand the mechanisms by which Nf1 regulates cell survival and proliferation in vivo. We have found that an ENU-induced point mutation (Nf1Dsk9) or a targeted knockout of one Nf1 allele specifically and uniformly darken the mouse skin dermis. The Endothelin receptor B (Ednrb) is essential for melanocyte (pigment producing cell) survival in the dermis between E10–E12.5. Since Nf1Dsk9 causes uniform hyper pigmentation of the dermis, we wanted to know whether Nf1Dsk9 depends on Ednrb signaling to cause dermal hyper pigmentation. In an attempt to understand the effect of homozygous loss of Nf1 on melanocytes, we knocked Nf1 out specifically in melanocytes. Methods: The Nf1Dsk9/+ mice were crossed to Ednrbs-l/s-l mice that have a complete deletion of the Ednrb gene. Pigmentation of the dermal tail skin and coat color spotting of 2–3 week old mice obtained from the above cross was quantified using ImageJ. A melanocyte-specific knockout of Nf1 was made in vivo in the mouse by crossing existing Mitf-Cre line to the floxed-Nf1 line. Pigmentation of the dermal tail skin was quantified using ImageJ. Results: A significant (p< 0.05, T-Test) hyper pigmentation of the dermis was observed in the Mitf-Cre/+; Nf1flox/flox homozygotes (now called Nf1mcko/mcko) with no change in epidermal pigmentation. In contrast to the Nf1Dsk9/+(germline heterozygote), the Nf1mcko/+ (melanocyte-specific knockout heterozygote) does not show dermal hyper pigmentation. Comparison of the tail dermis of Nf1Dsk9/+;Ednrbs-l/s-l mice with +/+;Ednrbs-l/s-l mice showed that Nf1Dsk9 was unable to give a dark dermis in the absence of Ednrb. However, the Nf1Dsk9/+;Ednrbs-l/s-l mice showed a significant (p< 0.05, T-Test) increase in the percentage of coat that was pigmented. Discussion: A significant darkening of the dermis in the Nf1mcko/mcko compared to wild type or Nf1mcko/+ littermates suggests a cell autonomous mechanism of dermal hyper pigmentation in the homozygote caused by the loss of Nf1 in melanocytes. The Nf1mcko/+ heterozygote does not show dermal hyper pigmentation, unlike the Nf1Dsk9/+ heterozygote. This suggests that the effect of loss of Nf1 in melanocytes acts in a non-cell autonomous mechanism in the heterozygote. The lack of dermal hyper pigmentation but an increased percentage of coat color spotting in the Nf1Dsk9/+;Ednrbs-l/s-l mice suggests that Nf1 regulates pigmentation by two independent mechanisms, one that depends on Ednrb and one that does not. Citation Information: Cancer Res 2009;69(23 Suppl):B59.
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