Ectopic expression of the nude gene induces hyperproliferation and defects in differentiation:: Implications for the self-renewal of cutaneous epithelia
Ectopic expression of the nude gene induces hyperproliferation and defects in differentiation:: Implications for the self-renewal of cutaneous epithelia
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DOI：
10.1006/dbio.1999.9328
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发表时间：
1999-08-01
影响因子：
2.7
通讯作者：
Brissette, JL
中科院分区：
文献类型：
--
作者：
Prowse, DM;Lee, D;Brissette, JL
裸鼠的特征是没有可见的毛发，表皮缺陷，以及不能发育胸腺。这种表型是有翼螺旋转录因子WHN(Hfh11)功能缺失突变的结果。在小鼠的表皮和毛囊中，当上皮细胞启动终末分化时，内源性WN的表达被诱导。利用分化标记总蛋白的启动子，产生了在复层鳞状上皮、毛囊和尿路移行上皮中异位表达wn的转基因小鼠。转基因的表皮和毛囊显示出末端分化受损，以及与转化生长因子-α表达降低相关的一系列毛发缺陷，如生长迟缓、波浪状被毛和卷曲的胡须。外源性WHN蛋白也能刺激上皮细胞增殖。在表皮中，基底层角质形成细胞表现出高度增殖，尽管转基因表达仅限于基底层上的有丝分裂后细胞。毛囊未能进入休眠期(休眠期)，并持续处于异常生长期(毛发周期的生长阶段)。输尿管上皮严重增生，导致尿流出道梗阻和肾积水死亡。虽然在转基因皮肤中偶尔会有免疫渗入，但这种渗入并不是导致上皮细胞过度增殖的主要原因，因为在所有受影响的转基因小鼠中并没有观察到免疫反应，而且转基因引起了免疫缺陷Rag1基因缺失小鼠相同的皮肤和尿路异常。鉴于转基因对细胞增殖和转化生长因子α表达的影响，结果表明WHN通过分化上皮细胞来调节生长因子的产生，从而调节自我更新上皮中增殖和有丝分裂后群体之间的平衡。(C)1999年学术出版社。
Nude mice are characterized by the absence of visible hair, epidermal defects, and the failure to develop a thymus. This phenotype results from loss-of-function mutations in Whn (Hfh11), a winged-helix transcription factor. In murine epidermis and hair follicles, endogenous whn expression is induced as epithelial cells initiate terminal differentiation. Using the promoter for the differentiation marker involucrin, transgenic mice that ectopically express whn in stratified squamous epithelia, hair follicles, and the transitional epithelium of the urinary tract were generated. Transgenic epidermis and hair follicles displayed impaired terminal differentiation and a subset of hair defects, such as delayed growth, a waved coat, and curly whiskers, correlated with decreased transforming growth factor (TGF)-alpha expression. The exogenous Whn protein also stimulated epithelial cell multiplication. In the epidermis, basal keratinocytes exhibited hyperproliferation, though transgene expression was restricted to suprabasal, postmitotic cells. Hair follicles failed to enter telogen (a resting period) and remained continuously in an abnormal anagen (the growth phase of the hair cycle). Ureter epithelium developed severe hyperplasia, leading to the obstruction of urine outflow and death from hydronephrosis. Though an immune infiltrate was present occasionally in transgenic skin, the infiltrate was not the primary cause of the epithelial hyperproliferation, as the immune reaction was not observed in all affected transgenics, and the transgene induced identical skin and urinary tract abnormalities in immunodeficient Rag1-null mice. Given the effects of the transgene on cell proliferation and TGF alpha expression, the results suggest that Whn modulates growth factor production by differentiating epithelial cells, thereby regulating the balance between proliferative and postmitotic populations in self-renewing epithelia. (C) 1999 Academic Press.