Generation and validation of mice carrying a conditional allele of the epidermal growth factor receptor.
Generation and validation of mice carrying a conditional allele of the epidermal growth factor receptor.
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DOI：
10.1002/dvg.20464
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发表时间：
2009-03
期刊：
影响因子：
1.5
通讯作者：
Threadgill, David W.
中科院分区：
文献类型：
--
作者：
Lee, Tang-Cheng;Threadgill, David W.
表皮生长因子受体（EGFR）对于多种组织中的正常稳态是重要的，并且当异常表达或突变时，有助于许多疾病的发展。然而，由于EGFR缺陷小鼠的出生前和出生后致死性，缺乏缺乏EGFR的成年小鼠阻碍了体内功能研究。我们产生了一个条件性等位基因Egfr（Egfrtm 1Dwt）侧翼外显子3 loxP网站，以调查这种广泛表达的受体酪氨酸激酶的组织特异性功能。Egfrtm 1Dwt等位基因的活性与野生型Egfr没有区别。相反，EgfrΔ等位基因，使用种系EIIa-Cre转基因系通过Cre介导的外显子3缺失产生，作为无效等位基因发挥作用。EGFR活性完全消除并在妊娠中期死亡的EgfrΔ/Δ胚胎，其胎盘缺陷与Egfrtm 1 Mag无效等位基因纯合子小鼠报告的胎盘缺陷相同。我们还使用K14-Cre转基因系在皮肤上皮中使Egfrtm 1Dwt等位基因组织特异性失活。这些小鼠存活，但表现出波浪状被毛，与Egfrwa 2亚型等位基因纯合子或Egfrwa 5反型等位基因杂合子小鼠非常相似。这些结果表明，无毛表型的Egfr基因缺失小鼠不仅是由于表皮细胞中没有EGFR，但EGFR的活性也需要在皮肤基质细胞的正常毛发形态发生。这种新的小鼠模型应具有广泛的实用性，有条件地抑制EGFR在成人组织和疾病状态的功能分析。
The epidermal growth factor receptor (EGFR) is important for normal homeostasis in a variety of tissues and, when abnormally expressed or mutated, contributes to the development of many diseases. However, in vivo functional studies are hindered by the lack of adult mice lacking EGFR because of the pre- and postnatal lethality of EGFR deficient mice. We generated a conditional allele of Egfr (Egfrtm1Dwt) by flanking exon 3 with loxP sites in order to investigate tissue-specific functions of this widely expressed receptor tyrosine kinase. The activity of the Egfrtm1Dwt allele is indistinguishable from wildtype Egfr. Conversely, the EgfrΔ allele, generated by Cre-mediated deletion of exon 3 using the germline EIIa-Cre transgenic line, functions as a null allele. EgfrΔ/Δ embryos that have complete ablation of EGFR activity and die at mid-gestation with placental defects identical to those reported for mice homozygous for the Egfrtm1Mag null allele. We also inactivated the Egfrtm1Dwt allele tissue-specifically in the skin epithelium using the K14-Cre transgenic line. These mice were viable but exhibited wavy coat hair remarkably similar to mice homozygous for the Egfrwa2 hypomorphic allele or heterozygous for the EgfrWa5 antimorphic allele. These results suggest that the hairless phenotype of Egfr nullizygous mice is not solely due to absence of EGFR in the epithelium, but that EGFR activity is required also in skin stromal cells for normal hair morphogenesis. This new mouse model should have wide utility to inactivate Egfr conditionally for functional analysis of EGFR in adult tissues and disease states.
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