Department of Physiology and Pharmacology, Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada.
Department of Physiology and Pharmacology, Children's Health Research Institute, Lawson Health Research Institute, London, Ontario, Canada; Department of Oncology, University of Western Ontario, London, Ontario, Canada.
J Invest Dermatol. 2020 Feb;140(2):425-434.e10. doi: 10.1016/j.jid.2019.07.681. Epub 2019 Jul 19.
Melanocytes are pigment-producing cells found in the skin and other tissues. Alterations in the melanocyte lineage give rise to a plethora of human diseases, from neurocristopathies and pigmentation disorders to melanoma. During embryogenesis, neural crest cell subsets give rise to two waves of melanoblasts, which migrate dorsolaterally, hone to the skin, and differentiate into melanocytes. However, the mechanisms that govern colonization of the skin by the first wave of melanoblasts are poorly understood. Here we report that targeted inactivation of the integrin-linked kinase gene in first wave melanoblasts causes defects in the ability of these cells to form long pseudopods, to migrate, and to proliferate in vivo. As a result, integrin-linked kinase-deficient melanoblasts fail to populate normally the developing epidermis and hair follicles. We also show that defects in motility and dendricity occur upon integrin-linked kinase gene inactivation in mature melanocytes, causing abnormalities in cell responses to the extracellular matrix substrates collagen I and laminin 332. Significantly, the ability to form long protrusions in mutant cells in response to collagen is restored in the presence of constitutively active Rac1, suggesting that an integrin-linked kinase-Rac1 nexus is likely implicated in melanocytic cell establishment, dendricity, and functions in the skin.
黑素细胞是存在于皮肤和其他组织中的产生色素的细胞。黑素细胞谱系的改变导致了许多人类疾病，从神经嵴疾病和色素沉着障碍到黑色素瘤。在胚胎发生过程中，神经嵴细胞亚群产生两波黑素细胞前体细胞，它们向背外侧迁移，向皮肤归巢，并分化为黑素细胞。然而，控制第一波黑素细胞前体细胞在皮肤中的定植的机制还知之甚少。在这里，我们报告说，在第一波黑素细胞前体细胞中靶向敲除整合素连接激酶基因会导致这些细胞形成长伪足、迁移和在体内增殖的能力缺陷。结果，整合素连接激酶缺陷型黑素细胞前体细胞不能正常地在发育中的表皮和毛囊中定植。我们还表明，在成熟的黑素细胞中整合素连接激酶基因失活会导致运动和树突状缺陷，从而导致细胞对细胞外基质底物胶原 I 和层粘连蛋白 332 的反应异常。重要的是，在胶原存在的情况下，突变细胞形成长突起的能力在组成性激活 Rac1 的情况下得以恢复，这表明整合素连接激酶-Rac1 连接很可能参与了黑素细胞的建立、树突状和皮肤功能。
