Adenomatous polyposis coli (APC) is required for normal development of skin and thymus.
Adenomatous polyposis coli (APC) is required for normal development of skin and thymus.
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DOI：
10.1371/journal.pgen.0020146
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发表时间：
2006-09-15
期刊：
影响因子：
4.5
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中科院分区：
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肿瘤抑制基因APC(腺瘤性息肉病)是Wnt信号通路中的一员，参与肿瘤的发生和发展。APC杂合基因敲除小鼠具有肿瘤易感性表型，纯合子导致胚胎死亡。为了了解APC在发育中的作用，我们产生了一个花等位基因。这些小鼠在人角蛋白14(K14)启动子的控制下与携带Cre重组酶的菌株交配，K14启动子在表皮和其他复层上皮的基底细胞中活跃。携带K14-cre转基因的纯合子等位基因的小鼠仍然存活，但生长发育迟缓，并在断奶前死亡。组织学和免疫化学检查显示，K14-cre介导的APC缺失导致许多外胚层来源的鳞状上皮异常生长，包括毛囊、牙齿、口腔和角膜上皮。此外，在包括胸腺在内的各种上皮源性组织中也观察到鳞状化生。K14-cre中毛囊和其他附件的异常生长以及胸腺的异常；ApcCKO/CKO小鼠表明APC基因在胚胎细胞中至关重要，以决定器官中需要上皮-间充质相互作用才能发育的上皮细胞的命运。家族性腺瘤性息肉病(FAP)及其变种加德纳综合征的患者将发展为数百例结直肠息肉。这是一种可遗传的疾病，与肿瘤抑制基因APC(结肠腺瘤性息肉病)的基因突变有关。这些人还会出现结肠外症状，其中包括先天性视网膜色素上皮肥大、硬纤维瘤、表皮样囊肿、上颌骨和骨骼的紊乱以及牙齿异常，这表明APC功能在这些器官中的重要性。为了了解APC在发育和肠道以外的器官中的作用，我们产生了APC突变小鼠，当暴露于Cre重组酶时，这些小鼠可以有条件地删除该基因。这些小鼠与在皮肤及其附件中表达Cre重组酶的K14(角蛋白14)-cre小鼠交配。作者发现，在K14-cre转基因表达组织中失去APC的突变小鼠是存活的，但生长发育迟缓，并在断奶前死亡。这些突变的小鼠不仅在皮肤上表现出发育异常，而且在包括牙齿和胸腺在内的许多上皮组织中也表现出发育异常。这项工作证明了APC在许多器官发育中的重要性，并为APC突变患者的诊断和处理提供了新的见解。
The tumor suppressor gene Apc (adenomatous polyposis coli) is a member of the Wnt signaling pathway that is involved in development and tumorigenesis. Heterozygous knockout mice for Apc have a tumor predisposition phenotype and homozygosity leads to embryonic lethality. To understand the role of Apc in development we generated a floxed allele. These mice were mated with a strain carrying Cre recombinase under the control of the human Keratin 14 (K14) promoter, which is active in basal cells of epidermis and other stratified epithelia. Mice homozygous for the floxed allele that also carry the K14-cre transgene were viable but had stunted growth and died before weaning. Histological and immunochemical examinations revealed that K14-cre–mediated Apc loss resulted in aberrant growth in many ectodermally derived squamous epithelia, including hair follicles, teeth, and oral and corneal epithelia. In addition, squamous metaplasia was observed in various epithelial-derived tissues, including the thymus. The aberrant growth of hair follicles and other appendages as well as the thymic abnormalities in K14-cre; ApcCKO/CKO mice suggest the Apc gene is crucial in embryonic cells to specify epithelial cell fates in organs that require epithelial–mesenchymal interactions for their development. Patients with familial adenomatous polyposis (FAP) and its variant, Gardner's syndrome, will develop hundreds of colorectal polyps. It is a heritable disease that is linked to a genetic mutation in the tumor suppressor gene APC (adenomatous polyposis coli). These individuals also develop extracolonic symptoms, among which are congenital hypertrophy of the retinal pigment epithelium, desmoid tumors, epidermoid cysts, disorders of the maxillary and skeletal bones, and dental abnormalities, suggesting the importance of APC functions in these organs. To understand the role of Apc in development and in organs other than intestine, we generated Apc mutant mice that can conditionally delete the gene when exposed to Cre recombinase. These mice were mated with K14 (Keratin 14)–cre mice that express Cre recombinase in skin and its appendages. The authors found that the mutant mice that have lost Apc in K14-cre transgene–expressing tissues were viable, but had stunted growth and died before weaning. These mutant mice showed developmental abnormalities not only in skin but also in many epithelial-derived tissues, including teeth and thymus. This work demonstrates the importance of Apc in development of many organs, and provides new insights into diagnosis and management of patients with APC mutations.