Giangreco Adam, Jensen Kim B, Takai Yoshimi, Miyoshi Jun, Watt Fiona M
Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
Development. 2009 Oct;136(20):3505-14. doi: 10.1242/dev.038232.
Differential expression of cell adhesion molecules regulates stem cell location, self-renewal and lineage selection under steady state conditions and during tissue repair. We show that the intercellular adhesion protein nectin-like molecule 2 (Necl2) is highly expressed in bulge stem cells of adult human and mouse hair follicles. Overexpression of Necl2 in cultured human keratinocytes led to upregulation of calcium/calmodulin-associated Ser/Thr kinase (CASK), increased calcium-independent intercellular adhesion, and inhibition of cell motility and in vitro wound healing. Although the rate of cell proliferation was reduced, terminal differentiation was unaffected. To assess the role of Necl2 in vivo, we examined the epidermis of Necl2-null mice and developed transgenic mice that expressed Necl2 in the basal layer of murine epidermis. Necl2 overexpression led to a reduction in S-phase cells and an increase in quiescent cells retaining DNA label in the bulge. Although epidermal homeostasis appeared normal in both transgenic and knockout mice, wound healing was markedly delayed. Necl2 overexpression resulted in reduced proliferation and increased levels of CASK and E-cadherin at the leading edge of healing wounds, consistent with its effects in culture. Our results demonstrate that Necl2 is involved in regulating epidermal stem cell quiescence and location.
细胞黏附分子的差异表达在稳态条件下以及组织修复过程中调节干细胞的定位、自我更新和谱系选择。我们发现，细胞间黏附蛋白nectin样分子2（Necl2）在成人及小鼠毛囊的隆突干细胞中高度表达。在培养的人角质形成细胞中过表达Necl2会导致钙/钙调蛋白相关丝氨酸/苏氨酸激酶（CASK）上调，增加非钙依赖性细胞间黏附，并抑制细胞运动和体外伤口愈合。虽然细胞增殖速率降低，但终末分化未受影响。为了评估Necl2在体内的作用，我们检查了Necl2基因敲除小鼠的表皮，并培育了在小鼠表皮基底层表达Necl2的转基因小鼠。Necl2过表达导致S期细胞减少，隆突中保留DNA标记的静止细胞增加。虽然转基因小鼠和基因敲除小鼠的表皮稳态看起来正常，但伤口愈合明显延迟。Necl2过表达导致愈合伤口前沿的增殖减少，CASK和E-钙黏蛋白水平增加，这与其在培养中的作用一致。我们的结果表明，Necl2参与调节表皮干细胞的静止和定位。
