Cooperative and indispensable roles of endothelin 3 and KIT signalings in melanocyte development
Cooperative and indispensable roles of endothelin 3 and KIT signalings in melanocyte development
复制标题
DOI：
10.1002/dvdy.20340
复制
发表时间：
2005-06-01
影响因子：
2.5
通讯作者：
Kunisada, T
中科院分区：
文献类型：
--
作者：
Aoki, H;Motohashi, T;Kunisada, T
神经嵴源性前体细胞黑素细胞的发育取决于受体酪氨酸激酶 KIT 和 G 蛋白偶联内皮素受体 B (EDNRB) 通路的信号传导。这两种信号受体分子中任何一个的功能丧失突变都会导致胚胎中黑素细胞前体数量的丧失或显着减少，并最终导致毛色丧失。利用胚胎干 (ES) 细胞培养物在体外诱导黑素细胞分化，我们研究了黑素细胞整个发育过程中 EDNRB 信号传导的需求以及 KIT 信号传导的相关性。在从未分化的 ES 细胞诱导成熟黑素细胞所需的 21 天期间，内皮素 3 (EDN3)（EDNRB 的配体）会按照其存在时间的比例增加黑素细胞的数量。我们利用Kit(W-LacZ)/Kit(W-Lacz) ES细胞在体内测试了EDNRB信号对KIT信号的补偿作用，并证实皮肤中EDN3的异位表达减少了Kit(W57)/Kit(W57)MiCe的白斑。 KIT配体（KITL）和EDN3协同作用，在体外诱导黑素细胞分化；然而，通过使用 EDN3(-/-) ES 细胞和 EDNRB 拮抗剂 BQ788 实现的 EDNRB 信号完全缺失表明，所导致的黑素细胞发育失败并不能通过添加 KITL 进一步激活 KIT 信号来补偿。同时阻断EDNRB和KIT信号传导可以完全消除黑素细胞前体细胞，这表明早期黑素细胞前体细胞的维持或存活至少需要EDNRB或KIT信号传导的存在。 (c) 2005 年 Wiley-Liss, Inc.
The development of melanocytes from neural crest-derived precursor cells depends on signaling by the receptor tyrosine kinase KIT and the G protein-coupled endothelin receptor B (EDNRB) pathways. Loss-of-function mutations in either of these two signaling receptor molecules cause a loss or a marked reduction in the number of melanocyte precursors in the embryo and finally lead to loss of the coat color. Using cultures of embryonic stem (ES) cells to induce melanocyte differentiation in vitro, we investigated the requirement for EDNRB signaling during the entire developmental process of the melanocyte, in association with that for KIT signaling. During the 21-day period necessary for the induction of mature melanocytes from undifferentiated ES cells, endothelin 3 (EDN3), a ligand for EDNRB, increased the number of melanocytes in proportion to the period during which it was present. We tested the compensatory effect of EDNRB signaling on KIT signaling in vivo by using Kit(W-LacZ)/Kit(W-Lacz) ES cells and confirmed that the ectopic expression of EDN3 in the skin reduced the white spotting of Kit(W57)/Kit(W57)MiCe. KIT ligand (KITL) and EDN3 worked synergistically to induce melanocyte differentiation in vitro; however, the complete lack of EDNRB signaling attained by the use of EDN3(-/-) ES cells and an EDNRB antagonist, BQ788, revealed that the resulting failure of melanocyte development was not compensated by the further activation of KIT signaling by adding KITL. Simultaneous blockade of EDNRB and KIT signalings eliminated melanocyte precursors completely, suggesting that the maintenance or survival of early melanocyte precursors at least required the existence of either EDNRB or KIT signalings. (c) 2005 Wiley-Liss, Inc.