Prowse D M, Lee D, Weiner L, Jiang N, Magro C M, Baden H P, Brissette J L
Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, 02129, USA.
Dev Biol. 1999 Aug 1;212(1):54-67. doi: 10.1006/dbio.1999.9328.
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 TGFalpha 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.
裸鼠的特征是无毛、表皮缺陷以及胸腺发育不全。这种表型是由有翼螺旋转录因子Whn（Hfh11）功能丧失性突变导致的。在小鼠表皮和毛囊中，随着上皮细胞开始终末分化，内源性whn表达被诱导。利用分化标志物兜甲蛋白的启动子，构建了在分层鳞状上皮、毛囊和泌尿道移行上皮中异位表达whn的转基因小鼠。转基因表皮和毛囊显示终末分化受损，且出现了一系列毛发缺陷，如生长延迟、毛发卷曲和胡须卷曲，这些与转化生长因子（TGF）-α表达降低相关。外源性Whn蛋白还刺激上皮细胞增殖。在表皮中，基底角质形成细胞表现出过度增殖，尽管转基因表达仅限于基底上层的有丝分裂后细胞。毛囊未能进入休止期（静止期），而是持续处于异常的生长期（毛发周期的生长阶段）。输尿管上皮出现严重增生，导致尿液流出受阻，最终因肾积水死亡。尽管转基因皮肤中偶尔会出现免疫浸润，但这种浸润并非上皮细胞过度增殖的主要原因，因为并非所有受影响的转基因小鼠都观察到免疫反应，并且转基因在免疫缺陷的Rag1基因敲除小鼠中诱导出相同的皮肤和泌尿道异常。鉴于转基因对细胞增殖和TGFα表达的影响，结果表明Whn通过调节分化中的上皮细胞生长因子产生，从而调节自我更新上皮中增殖和有丝分裂后细胞群之间的平衡。
