Cell-autonomous and cell non-autonomous signaling through endothelin receptor B during melanocyte development
Cell-autonomous and cell non-autonomous signaling through endothelin receptor B during melanocyte development
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DOI：
10.1242/dev.01193
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发表时间：
2004-07-01
期刊：
影响因子：
4.6
通讯作者：
Arnheiter, H
中科院分区：
文献类型：
--
作者：
Hou, L;Pavan, WJ;Arnheiter, H
内皮素受体B基因（Ednr B）编码在多种细胞类型中表达的G蛋白偶联受体，并且是神经嵴衍生的黑素细胞和肠神经节发育所特别需要的。在人类中，该基因的突变与Waardenburg-Shah综合征有关，这是一种以色素沉着缺陷、耳聋和巨结肠为特征的疾病。为了解决黑素细胞的发育是否完全依赖于Ednrb的细胞自主行动的问题，我们进行了一系列的体外组织重组实验，使用神经嵴细胞培养物从小鼠胚胎携带一种新的Ednrb无效等位基因，其特征在于插入lacZ标记基因。结果表明，Ednrb不是产生早期神经嵴来源的成黑素细胞所必需的，但却是分化标志物酪氨酸酶表达所必需的。酪氨酸酶的表达可以获救，然而，通过添加Ednrb野生型神经管。这些Ednrb野生型神经管本身不需要能够产生黑素细胞，但必须能够提供KIT配体，酪氨酸激酶受体KIT的同源配体。事实上，可溶性KIT配体足以在Ednrb缺陷培养物中诱导酪氨酸酶表达。然而，这些酪氨酸酶表达的Ednrb缺陷细胞不发育为终末分化的色素黑素细胞。然而，通过用十四烷酰基佛波醇乙酸酯（其模拟EDNRB信号传导）处理可以诱导色素沉着，但通过用内皮素1（其刺激旁系同源受体EDNRA）处理不能诱导色素沉着。结果表明，Ednrb在黑素细胞分化过程中起着重要作用，并通过细胞非自主和细胞自主信号机制影响黑素细胞的发育。
The endothelin receptor B gene (Ednrb) encodes a G-protein-coupled receptor that is expressed in a variety of cell types and is specifically required for the development of neural crest-derived melanocytes and enteric ganglia. In humans, mutations in this gene are associated with Waardenburg-Shah syndrome, a disorder characterized by pigmentation defects, deafness and megacolon. To address the question of whether melanocyte development depends entirely on a cell-autonomous action of Ednrb, we performed a series of tissue recombination experiments in vitro, using neural crest cell cultures from mouse embryos carrying a novel Ednrb-null allele characterized by the insertion of a lacZ marker gene. The results show that Ednrb is not required for the generation of early neural crest-derived melanoblasts but is required for the expression of the differentiation marker tyrosinase. Tyrosinase expression can be rescued, however, by the addition of Ednrb wild-type neural tubes. These Ednrb wild-type neural tubes need not be capable of generating melanocytes themselves, but must be capable of providing KIT ligand, the cognate ligand for the tyrosine kinase receptor KIT. In fact, soluble KIT ligand is sufficient to induce tyrosinase expression in Ednrb-deficient cultures. Nevertheless, these tyrosinase-expressing, Ednrb-deficient cells do not develop to terminally differentiated, pigmented melanocytes. Pigmentation can be induced, however, by treatment with tetradecanoyl phorbol acetate, which mimics EDNRB signaling, but not by treatment with endothelin 1, which stimulates the paralogous receptor EDNRA. The results suggest that Ednrb plays a significant role during melanocyte differentiation and effects melanocyte development by both cell non-autonomous and cell-autonomous signaling mechanisms.