Vassar R, Fuchs E
Howard Hughes Medical Institute, Department of Molecular Genetics and Cell Biology, University of Chicago, Illinois 60637.
Genes Dev. 1991 May;5(5):714-27. doi: 10.1101/gad.5.5.714.
Transforming growth factor-alpha (TGF-alpha) is thought to be the major autocrine factor controlling growth in epidermal cells. To explore further the role of TGF-alpha in epidermal growth and differentiation, we used a human keratin K14 promoter to target expression of rat TGF-alpha cDNA to the stratified squamous epithelia of transgenic mice. Unexpectedly, the only regions of epidermis especially responsive to TGF-alpha overexpression were those that were normally thick and where hair follicle density was typically low. This included most, if not all, body skin from 2-day- to 2-week-old mice, and ear, footpad, tail, and scrotum skin in adult mice. In these regions, excess TGF-alpha resulted in thicker epidermis and more stunted hair growth. Epidermal thickening was attributed both to cell hypertrophy and to a proportional increase in the number of basal, spinous, granular, and stratum corneum cells. During both postnatal development and epidermal differentiation, responsiveness to elevated TGF-alpha seemed to correlate with existing epidermal growth factor (EGF) receptor levels, and we saw no evidence for TGF-alpha-mediated control of EGF receptor (EGFR) expression. In adults, no squamous cell carcinomas were detected, but benign papillomas were common, developing primarily in regions of mechanical irritation or wounding. In addition, adult transgenic skin that was still both sensitive to TGF-alpha and subject to mild irritation displayed localized regions of leukocytic infiltration and granular layer loss, characteristics frequently seen in psoriasis in humans. These unusual regional and developmental effects of TGF-alpha suggest a natural role for the growth factor in (1) controlling epidermal thickness during development and differentiation, (2) involvement in papilloma formation, presumably in conjunction with TGF-beta, and (3) involvement in psoriasis, in conjunction with some as yet unidentified secondary stimulus stemming from mild mechanical irritation/bacterial infection.
转化生长因子α（TGF-α）被认为是控制表皮细胞生长的主要自分泌因子。为了进一步探究TGF-α在表皮生长和分化中的作用，我们使用人类角蛋白K14启动子，将大鼠TGF-α cDNA的表达靶向到转基因小鼠的复层鳞状上皮。出乎意料的是，表皮中对TGF-α过表达特别有反应的唯一区域是那些通常较厚且毛囊密度通常较低的区域。这包括2日龄至2周龄小鼠的大部分（如果不是全部）身体皮肤，以及成年小鼠的耳部、足垫、尾巴和阴囊皮肤。在这些区域，过量的TGF-α导致表皮增厚和毛发生长更受抑制。表皮增厚归因于细胞肥大以及基底细胞、棘细胞、颗粒细胞和角质层细胞数量的成比例增加。在出生后发育和表皮分化过程中，对升高的TGF-α的反应性似乎与现有的表皮生长因子（EGF）受体水平相关，并且我们没有发现TGF-α介导的对EGF受体（EGFR）表达的控制证据。在成年小鼠中，未检测到鳞状细胞癌，但良性乳头状瘤很常见，主要发生在机械刺激或受伤区域。此外，对TGF-α仍敏感且受到轻度刺激的成年转基因皮肤显示出白细胞浸润和颗粒层缺失的局部区域，这是人类银屑病中常见的特征。TGF-α这些不寻常的区域和发育效应表明，该生长因子在以下方面具有天然作用：（1）在发育和分化过程中控制表皮厚度；（2）可能与TGF-β一起参与乳头状瘤形成；（3）与源于轻度机械刺激/细菌感染的一些尚未确定的二次刺激一起参与银屑病。
