PDF(Pubmed)
Abstract：
Hedgehog (Hh) signaling is well known for its crucial role during development, but its specific role in individual cell lineages is less well characterized. Here, we disrupted Hh signaling specifically in melanocytes by using Cre-mediated cell-type-specific knockout of the Hh regulator suppressor of fused (Sufu). Interestingly, corresponding mice were fully pigmented and showed no developmental alterations in melanocyte numbers or distribution in skin and hair follicles. However, there were ectopic melanoblasts visible in the anterior chamber of the eye that eventually displayed severe malformation. Choroidal melanocytes remained unaltered. Surprisingly, the abnormal accumulation of anterior uveal melanoblasts was not the result of increased cell proliferation but of increased migration to ectopic locations such as the cornea. In melanoblasts in vitro, Sufu knockdown replicated the increase in cell migration without affecting proliferation and was mediated by an increased level of phosphorylated-ERK brought about by a reduction in the levels of the repressor form of GLI3. These results highlight the developmental divergence of distinct melanocyte subpopulations and may shed light on the pathogenesis of human ocular melanocytosis.
摘要：
Hedgehog（Hh）信号在发育过程中的关键作用是众所周知的，但其在单个细胞谱系中的特定作用却没有得到很好的表征。在这里，我们通过使用Cre介导的Hh调节因子融合抑制因子（Sufu）的细胞类型特异性敲除策略来破坏黑素细胞中的Hh信号传导。有趣的是,相应的小鼠完全色素沉着，皮肤和毛囊中的黑素细胞数量或分布没有发育变化。然而,在眼前房中可见异位的黑素细胞，最终表现出严重的畸形。脉络膜黑素细胞保持不变。令人惊讶的是,葡萄膜前黑色素细胞的异常积累不是细胞增殖增加的结果，而是向角膜等异位位置迁移的增加。在体外的成黑素细胞中，Sufu敲低复制了细胞迁移的增加而不影响增殖，并且是由GLI3阻遏物形式的水平降低引起的磷酸化ERK水平的增加介导的。结果突出了不同黑素细胞亚群的发育差异，并可能阐明人类眼部黑素细胞增多症的发病机理。
