Neurofibromin as a regulator of melanocyte development and differentiation
Neurofibromin as a regulator of melanocyte development and differentiation
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DOI：
10.1242/jcs.013912
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发表时间：
2008-01-15
影响因子：
4
通讯作者：
Hornyak, Thomas J.
中科院分区：
文献类型：
--
作者：
Diwakar, Ganesh;Zhang, Deming;Hornyak, Thomas J.
患有遗传性疾病 I 型神经纤维瘤病 (NF1) 的患者表现出与 NF1 单个等位基因缺失相关的特征性色素病变，该等位基因编码 260 kDa 的神经纤维蛋白。为了了解这些色素问题的基础，使用 Nf1(+/-) 敲除小鼠研究了鼠基因 Nf1 单倍体不足的黑素细胞的特性。我们证明神经纤维蛋白在黑素细胞发育过程中调节体内 Kit-Mitf 信号轴。原代Nf1(+/-)黑素细胞通过FACS纯化以测量黑素基因表达。我们发现 Nf1(+/-) 黑素细胞比野生型黑素细胞表现出更高水平的黑素基因表达。在 Kit 刺激之前和之后，与原代细胞相比，Nf1(+/-) 黑素细胞也表现出 MAP 激酶途径激活增加。原代黑素细胞对 Mek 抑制的黑素生成反应与 Nf1 单倍体不足时观察到的变化一致；然而，这些变化与在不朽的对应物中观察到的变化不同。观察到神经纤维蛋白的减少，无论是由于原代黑素细胞的单倍体不足，还是由于黑色素-a细胞的神经纤维蛋白敲低，都会增强黑色素基因表达，这表明神经纤维蛋白在控制小鼠黑素细胞中的黑色素基因表达中对 MEK 活性起主导作用。
Patients with the genetic disease type I neurofibromatosis (NF1) exhibit characteristic pigmentary lesions associated with loss of a single allele of NF1, encoding the 260 kDa protein neurofibromin. To understand the basis for these pigmentary problems, the properties of melanocytes haploinsufficient for the murine gene Nf1 were studied using Nf1(+/-) knockout mice. We demonstrate that neurofibromin regulates the Kit-Mitf signaling axis in vivo during melanocyte development. Primary Nf1(+/-) melanocytes were purified by FACS to measure melanogenic gene expression. We found that Nf1(+/-) melanocytes exhibit higher levels of melanogenic gene expression than their wild-type counterparts. Both prior to and following Kit stimulation, Nf1(+/-) melanocytes also exhibit increased activation of the MAP kinase pathway compared with primary cells. The melanogenic response of primary melanocytes to Mek inhibition is consistent with the changes observed with Nf1 haploinsufficiency; however, these changes differ from those observed with their immortalized counterparts. The observation that reduction of neurofibromin, either from haploinsufficiency in the case of primary melanocytes or from neurofibromin knockdown in the case of melan-a cells, enhances melanogenic gene expression suggests that neurofibromin plays a dominant role to MEK activity in controlling melanogenic gene expression in murine melanocytes.