Both Notch1 and Notch2 contribute to the regulation of melanocyte homeostasis
Both Notch1 and Notch2 contribute to the regulation of melanocyte homeostasis
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DOI：
10.1111/j.1755-148x.2007.00423.x
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发表时间：
2008-02-01
影响因子：
4.3
通讯作者：
Chiba, Shigeru
中科院分区：
文献类型：
--
作者：
Kumano, Keiki;Masuda, Shigeo;Chiba, Shigeru
Notch信号传导影响多种哺乳动物干细胞，但有有限的证据表明，特定的Notch分子调节成体干细胞。最近，据报道，在胚胎阶段开始的减少的Notch信号传导导致出生后逐渐变白的毛发表型。在这里，我们证明，口服给药的γ-分泌酶抑制剂（GSI）的野生型成年C57/BI 6小鼠导致灰色斑点逐渐增加，这保持不变，至少20周后停止GSI。在GSI处理的小鼠中，黑素细胞干细胞所在的隆起/亚隆起区域中的无色素黑素细胞严重减少。虽然我们证实了具有C57/BI 6背景的Notch 1 +/-Notch 2 +/-双杂合小鼠出生时具有正常的毛发颜色表型，并且在第二个毛发周期后逐渐变灰，但在c-kit突变体Wv背景中，Notch 1 +/-和Notch 2 +/-小鼠在首次出现毛发时具有比Wv/+小鼠更大的白色斑点，其在整个生命过程中没有变化。Notch 1 +/-Notch 2 +/- Wv/+小鼠在第一次出现毛发时几乎全身都有白色毛发，此后色素脱失继续进展。使用神经嵴器官培养系统，GSI阻断了色素黑素细胞的产生时，加入到培养期间的成黑素细胞增殖，但不是在分化期间。这些观察结果表明Notch信号在胚胎发生期间黑素细胞的发育和成年期黑素细胞干细胞的维持中的作用，而在这些环境中的需求程度是不同的：后者比前者对减少的Notch信号更敏感。此外，Notch 1和Notch 2在胚胎发生过程中与c-kit信号传导合作，并且它们在出生后相互合作以调节黑素细胞的稳态。
Notch signaling affects a variety of mammalian stem cells, but there has been limited evidence that a specific Notch molecule regulates adult stem cells. Recently, it was reported that the reduced Notch signaling initiated at the embryonic stage results in a gradual hair graying phenotype after birth. Here we demonstrate that the oral administration of a gamma-secretase inhibitor (GSI) to wild-type adult C57/BI6 mice led to a gradual increase in gray spots, which remained unchanged for at least 20 weeks after discontinuing the GSI. In GSI-treated mice, there was a severe decrease in unpigmented melanocytes in the bulge/subbulge region where melanocyte stem cells are located. While we confirmed that Notch1+/-Notch2+/- double heterozygous mice with a C57/BI6 background were born with a normal hair color phenotype and gradually turned gray after the second hair cycle, in the c-kit mutant Wv background, Notch1+/- and Notch2+/- mice had larger white spots on the first appearance of hair than did the Wv/+ mice, which did not change throughout life. Notch1+/- Notch2+/- Wv/+ mice had white hair virtually all over the body at the first appearance of hair and the depigmentation continued to progress thereafter. Using a neural crest organ culture system, GSI blocked the generation of pigmented melanocytes when added to the culture during the period of melanoblast proliferation, but not during the period of differentiation. These observations imply roles of Notch signaling in both development of melanocyte during embryogenesis and maintenance of melanocyte stem cells in adulthood, while the degree of requirement is distinct in these settings: the latter is more sensitive than the former to the reduced Notch signaling. Furthermore, Notch1 and Notch2 cooperates with c-kit signaling during embryogenesis, and they cooperate with each other to regulate melanocyte homeostasis after birth.