Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo.
Genetic dissection of differential signaling threshold requirements for the Wnt/beta-catenin pathway in vivo.
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DOI：
10.1371/journal.pgen.1000816
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发表时间：
2010-01-15
期刊：
影响因子：
4.5
通讯作者：
Ernst M
中科院分区：
文献类型：
--
作者：
Buchert M;Athineos D;Abud HE;Burke ZD;Faux MC;Samuel MS;Jarnicki AG;Winbanks CE;Newton IP;Meniel VS;Suzuki H;Stacker SA;Näthke IS;Tosh D;Huelsken J;Clarke AR;Heath JK;Sansom OJ;Ernst M
空和亚纯型等位基因的APC在小鼠中产生发育和病理生理表型。为了将所得到的基因型与表型的关系明确地归因于Wnt/β-连环蛋白途径，我们通过在相应的复合突变小鼠中遗传限制细胞内β-连环蛋白表达来挑战等位基因组合。随后对小鼠胚胎成纤维细胞中产生的Tcf 4-报告基因活性的程度进行评估，使得能够以小鼠突变体的等位基因系列的形式对Wnt/β-连环蛋白信号传导进行遗传测量。不同的允许Wnt信号传导阈值似乎是头部结构的胚胎发育、成人肠息肉病、肝细胞癌、肝分区和自然杀伤细胞发育所需的。此外，我们鉴定了一种纯合Apc等位基因组合，其Wnt/β-连环蛋白信号传导能力与Apcmin小鼠的种系中的相似，其中体细胞Apc杂合性缺失触发肠息肉病，以区分Apcmin小鼠中的共病是否独立于肠肿瘤发生而出现。总之，目前的基因型-表型分析表明，Wnt/β-连环蛋白途径的组织特异性反应水平调节生理和病理生理条件。基因中的生殖系或体细胞突变是许多人类疾病的根本原因，最显著的是癌症。有趣的是，即使在生物体的每个组织的每个细胞都携带相同突变的情况下（如种系突变的情况），随着时间的推移，某些组织比其他组织更容易发生疾病。例如，在家族性腺瘤性息肉病（FAP）中，受影响的人在APC基因中携带不同的种系突变，并且易于发展为结肠癌和直肠癌，并且较少发生在其他组织中的癌症，如胃，肝和骨骼。在这里，我们利用了一组突变小鼠的截短或亚纯型突变的APC基因，导致不同水平的激活Wnt/β-连环蛋白途径。我们的研究结果表明，不同的病理生理结果取决于不同的许可信号阈值在胚胎，肠，肝组织。重要的是，我们证明，减少50%的Wnt通路激活足以防止成年小鼠胚胎异常和疾病的表现。这就提出了开发治疗策略的可能性，这些策略可以调节该途径的激活水平，而不是试图“修复”基因本身的突变。
Contributions of null and hypomorphic alleles of Apc in mice produce both developmental and pathophysiological phenotypes. To ascribe the resulting genotype-to-phenotype relationship unambiguously to the Wnt/β-catenin pathway, we challenged the allele combinations by genetically restricting intracellular β-catenin expression in the corresponding compound mutant mice. Subsequent evaluation of the extent of resulting Tcf4-reporter activity in mouse embryo fibroblasts enabled genetic measurement of Wnt/β-catenin signaling in the form of an allelic series of mouse mutants. Different permissive Wnt signaling thresholds appear to be required for the embryonic development of head structures, adult intestinal polyposis, hepatocellular carcinomas, liver zonation, and the development of natural killer cells. Furthermore, we identify a homozygous Apc allele combination with Wnt/β-catenin signaling capacity similar to that in the germline of the Apcmin mice, where somatic Apc loss-of-heterozygosity triggers intestinal polyposis, to distinguish whether co-morbidities in Apcmin mice arise independently of intestinal tumorigenesis. Together, the present genotype–phenotype analysis suggests tissue-specific response levels for the Wnt/β-catenin pathway that regulate both physiological and pathophysiological conditions. Germline or somatic mutations in genes are the underlying cause of many human diseases, most notably cancer. Interestingly though, even in situations where every cell of every tissue of an organism carries the same mutation (as is the case for germline mutations), some tissues are more susceptible to the development of disease over time than others. For example, in familial adenomatous polyposis (FAP), affected persons carry different germline mutations in the APC gene and are prone to developing cancers of the colon and the rectum—and, less frequently, cancers in other tissues such as stomach, liver, and bones. Here we utilize a panel of mutant mice with truncating or hypomorphic mutations in the Apc gene, resulting in different levels of activation of the Wnt/β-catenin pathway. Our results reveal that different pathophysiological outcomes depend on different permissive signaling thresholds in embryonic, intestinal, and liver tissues. Importantly, we demonstrate that reducing Wnt pathway activation by 50% is enough to prevent the manifestation of embryonic abnormalities and disease in the adult mouse. This raises the possibility of developing therapeutic strategies that modulate the activation levels of this pathway rather than trying to “repair” the mutation in the gene itself.
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