Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden.
Development. 2012 Jan;139(2):397-410. doi: 10.1242/dev.065581.
The cellular origin and molecular mechanisms regulating pigmentation of head and neck are largely unknown. Melanocyte specification is controlled by the transcriptional activity of Mitf, but no general logic has emerged to explain how Mitf and progenitor transcriptional activities consolidate melanocyte and progenitor cell fates. We show that cranial melanocytes arise from at least two different cellular sources: initially from nerve-associated Schwann cell precursors (SCPs) and later from a cellular source that is independent of nerves. Unlike the midbrain-hindbrain cluster from which melanoblasts arise independently of nerves, a large center of melanocytes in and around cranial nerves IX-X is derived from SCPs, as shown by genetic cell-lineage tracing and analysis of ErbB3-null mutant mice. Conditional gain- and loss-of-function experiments show genetically that cell fates in the neural crest involve both the SRY transcription factor Sox2 and Mitf, which consolidate an SCP progenitor or melanocyte fate by cross-regulatory interactions. A gradual downregulation of Sox2 in progenitors during development permits the differentiation of both neural crest- and SCP-derived progenitors into melanocytes, and an initial small pool of nerve-associated melanoblasts expands in number and disperses under the control of endothelin receptor B (Ednrb) and Wnt5a signaling.
头颈部的皮肤色素沉着的细胞起源和分子机制在很大程度上是未知的。黑素细胞的特化受转录因子 Mitf 的转录活性控制，但尚无一般的逻辑来解释 Mitf 和祖细胞转录活性如何巩固黑素细胞和祖细胞的命运。我们表明，颅黑素细胞至少有两种不同的细胞来源：最初来源于与神经相关的 Schwann 细胞前体细胞（SCPs），后来来源于与神经无关的细胞来源。与从中枢神经系统独立产生黑素细胞的中脑-后脑簇不同，神经 IX-X 周围和内部的大量黑素细胞来源于 SCPs，这可以通过遗传细胞谱系追踪和对 ErbB3 缺失突变体小鼠的分析来证明。条件性获得和丧失功能实验表明，神经嵴中的细胞命运既涉及 SRY 转录因子 Sox2，也涉及 Mitf，通过交叉调节相互作用来巩固 SCP 祖细胞或黑素细胞命运。在发育过程中，Sox2 在祖细胞中的逐渐下调允许神经嵴和 SCP 衍生的祖细胞分化为黑素细胞，最初一小部分与神经相关的黑素细胞在内皮素受体 B（Ednrb）和 Wnt5a 信号的控制下数量增加并分散。
