Differential Effects of Neurofibromin Gene Dosage on Melanocyte Development
Differential Effects of Neurofibromin Gene Dosage on Melanocyte Development
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DOI：
10.1038/jid.2012.240
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发表时间：
2013-01-01
影响因子：
6.5
通讯作者：
Van Raamsdonk, Catherine D.
中科院分区：
文献类型：
--
作者：
Deo, Mugdha;Huang, Jenny Li-Ying;Van Raamsdonk, Catherine D.
神经纤维蛋白(NF1)基因突变导致1型神经纤维瘤病的显性遗传性疾病。神经纤维瘤病的特征是以雪旺细胞为基础的肿瘤和皮肤色素沉着，原因是单倍体不足和杂合性丢失。事实上，一些色素细胞(黑素细胞)来自雪旺细胞前体，这表明在共同的前体阶段可能需要神经纤维素。在这项研究中，我们在暗皮肤9(Dsk9)突变小鼠中发现了神经纤维蛋白的nnisense突变，揭示了Nf1突变会导致小鼠皮肤色素沉着，就像它们对人类所做的那样。使用组织特异性基因敲除，我们发现通过MITF-cre在黑素细胞中神经纤维蛋白单倍性不足不足以导致皮肤变黑，而通过Plp1-Creer在双潜能雪旺细胞-黑素母细胞前体中单倍性不足就足够了。这些发现表明，有一个狭窄的发育窗口，在此期间，NF1单倍体不足作用于色素细胞。利用命运图，我们发现了黑素细胞在真皮和表皮的定植方面的差异，这些黑素细胞起源于雪旺细胞前体，这是黑素细胞发育的一种意想不到的复杂性。由于通过MITF-cre纯合子敲除NF1足以导致皮肤变黑，我们得出结论，减少基因剂量可以通过不同于完全基因丢失的机制发挥作用，即使两者的最终结果非常相似。《皮肤病研究杂志》(2013年)第133期，49-58期；doi：10.1038/jid.2012.240；2012年7月19日在线发表
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 (melanocyles) arise from Schwann cell precursors suggests that neurofibromin could be required during the common precursor stage. In this study, we found a nnissense 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. Journal of Investigative Dermatology (2013) 133, 49-58; doi:10.1038/jid.2012.240; published online 19 July 2012