PuSH - Publication Server of Helmholtz Zentrum München

Deo, M.* ; Huang, J. L.-Y.* ; Fuchs, H. ; Hrabě de Angelis, M. ; van Raamsdonk, C. D.*

Differential effects of neurofibromin gene dosage on melanocyte development.

J. Invest. Dermatol. 133, 49-58 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
Altmetric
Additional Metrics?
[➜Log in]
Edit extra informations Login
Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 0022-202X
e-ISSN 1523-1747
Journal Journal of Investigative Dermatology, The
Quellenangaben Volume: 133, Issue: 1, Pages: 49-58 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)