Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Miyagi 980-8575, Japan.
Genes Cells. 2012 Jun;17(6):494-508. doi: 10.1111/j.1365-2443.2012.01603.x. Epub 2012 May 7.
Microphthalmia-associated transcription factor (Mitf) is a regulator for differentiation of melanoblasts that are derived from the neural crest. The mouse homozygous for the black-eyed white (Mitf(mi-bw)) allele is characterized by the white coat color and deafness, with black eye that is associated with the lack of melanocytes in skin and inner ear. The Mitf(mi-bw) mutation is an insertion of the LINE1 retrotransposable element into intron 3 of the Mitf gene that causes the selective deficiency of the melanocyte-specific Mitf isoform, Mitf-M. Here, we show the expression of Mitf-M mRNA in the trunk region of the homozygous Mitf(mi-bw)(bw) mouse at embryonic days (E) 11.5 and E12.5, but Mitf-M mRNA is undetectable at E13.5. In addition, using bw mouse that carries the lacZ transgene under the control of a melanoblast-specific promoter, we show that the number of migrating melanoblasts in bw embryos was less than 10% of that in control embryos at E11.5 and E12.5, and melanoblasts disappear by E13.5. The loss of melanoblasts in bw embryos was probably caused by apoptosis. Finally, forced expression of Mitf-M in the cultured neural tube of bw embryos ensured the differentiation of melanoblasts. Therefore, the correct dose of Mitf-M is required for the normal development of melanoblasts.
小眼畸形相关转录因子（Mitf）是神经嵴来源的黑素细胞分化的调节因子。纯合的黑眼睛白化（Mitf(mi-bw)）等位基因的小鼠表现为白色皮毛和耳聋，其黑色眼睛与皮肤和内耳中缺乏黑素细胞有关。Mitf(mi-bw)突变是 LINE1 反转录转座子插入 Mitf 基因的 3 号内含子，导致黑素细胞特异性 Mitf 同工型 Mitf-M 的选择性缺乏。在这里，我们在 E11.5 和 E12.5 胚胎日的纯合 Mitf(mi-bw)(bw)小鼠的躯干区域显示 Mitf-M mRNA 的表达，但在 E13.5 时 Mitf-M mRNA 无法检测到。此外，我们使用携带受黑素细胞特异性启动子控制的 lacZ 转基因的 bw 小鼠，显示 bw 胚胎中迁移的黑素细胞数量在 E11.5 和 E12.5 时不到对照胚胎的 10%，并且黑素细胞在 E13.5 时消失。bw 胚胎中黑素细胞的丢失可能是由细胞凋亡引起的。最后，在 bw 胚胎的培养神经管中强制表达 Mitf-M 可确保黑素细胞的分化。因此，黑素细胞的正常发育需要正确剂量的 Mitf-M。
