Differential Effects of Neurofibromin Gene Dosage on Melanocyte Development

Abstract

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.

Oncogenic G Protein GNAQ Induces Uveal Melanoma and Intravasation in Mice

“…It is not known why lesions located in the epidermis and dermis exhibit different mutational signatures, although there are several possibilities. First, there could be intrinsic or developmental differences among melanocytes colonizing different parts of the skin (36,50). Second, there could be different paracrine signals emanating from keratinocytes versus fibroblasts, surrounding melanocytes in the epidermis and dermis, respectively.…”

“…The cause of these phenotypes is unknown (31). Mitf-cre is expressed in epidermal, dermal, and follicular melanocytes of the tail and trunk skin (31,36). Expression in uveal, otic, and leptomeningeal melanocytes of the central nervous system (CNS) and spinal cord has not been previously reported.…”

“…Mitf-cre is the earliest Cre driver expressed specifically in melanocytes. Mitf-cre has an efficiency of 25% at E15.5 (36) and 68% at P40 (Supplementary Table S1). On the C3HeB/FeJ genetic background, Mitf-cre animals are smaller than nontransgenic animals (Supplementary Fig.…”

The NF1 gene in tumor syndromes and melanoma

“…The Nf1 +/− melanocytes also display increased melanogenic gene expression and enhanced Kit-dependent and Kit-independent ERK activity. Additionally, mice with homozygous knock-out of Nf1 in melanocytes show hyperpigmented skin 67 .…”

In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

“…Mouse models of the disease were difficult to generate, because homozygous Nf1 −/− mice died in utero (16) and Nf1 +/− mice manifested neither pigmentation abnormalities nor neurofibromas (17,18). The hyperpigmentation phenotype has been reproduced using a specific knock-down of Nf1 in bipotential Schwann cellmelanoblast precursors (19), but molecular mechanisms linking neurofibromin to defective pathways in melanocytes have not been fully identified. The relevance of the mouse model might be questionable in any case, given that mouse melanocytes localize in hair follicles and not in the epidermis as in human melanocytes.…”