Betacellulin overexpression in transgenic mice causes disproportionate growth, pulmonary hemorrhage syndrome, and complex eye pathology
Betacellulin overexpression in transgenic mice causes disproportionate growth, pulmonary hemorrhage syndrome, and complex eye pathology
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DOI：
10.1210/en.2005-0418
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发表时间：
2005-12-01
期刊：
影响因子：
4.8
通讯作者：
Wolf, E
中科院分区：
文献类型：
--
作者：
Schneider, MR;Dahlhoff, M;Wolf, E
EGF家族包括一个配体和受体网络，调节正常发育，并在生理和病理学中引起不同的功能。Betacellulin（BTC）是EGF家族的一个相当缺乏特征的成员，其体内作用主要与内分泌胰腺，肠道和乳腺功能有关。体外研究表明，这种生长因子是多种细胞类型的有效促分裂剂，并具有独特的受体结合特性。BTC在小鼠中的基因消融产生了轻度表型，可能是因为其他EGF受体配体的机会性补偿。为了研究BTC在体内的生物学能力，我们产生了普遍过表达BTC的转基因小鼠，其在心脏、肺、脑和胰腺中的表达水平最高。过表达BTC的小鼠表现出高的出生后早期死亡率，体重增加减少，纵向生长受损。此外，还观察到多种病理学改变。白内障和异常形状的视网膜层以及导致圆顶形、圆头形的骨改变是BTC转基因小鼠的标志。最重要的发现和BTC转基因小鼠预期寿命缩短的原因是肺部的严重改变。肺病理学的主要特征是肺泡出血、肺泡间隔增厚、含铁血黄素巨噬细胞在肺泡内积聚和结节性肺重塑。因此，我们的模型揭示了体内BTC过度表达的多种后果。这些转基因小鼠为研究BTC过量对不同器官的影响提供了有用的模型。
The EGF family comprises a network of ligands and receptors that regulate proper development and elicit diverse functions in physiology and pathology. Betacellulin (BTC) is a rather poorly characterized member of the EGF family whose in vivo effects have been linked mainly to endocrine pancreas, intestine, and mammary gland function. In vitro studies revealed that this growth factor is a potent mitogen for diverse cell types and suggested unique receptor-binding properties. Genetic ablation of BTC in mice yielded a mild phenotype, probably because of opportunistic compensation by other EGF receptor ligands. To study the biological capabilities of BTC in vivo, we generated transgenic mice overexpressing BTC ubiquitously, with highest expression levels in heart, lung, brain, and pancreas. Mice overexpressing BTC exhibit high early postnatal mortality, reduced body weight gain, and impaired longitudinal growth. In addition, a variety of pathological alterations were observed. Cataract and abnormally shaped retinal layers as well as bone alterations leading to a dome-shaped, round head form were hallmarks of BTC transgenic mice. The most important finding and the cause of reduced life expectancy of BTC transgenic mice were severe alterations of the lung. Pulmonary pathology was primarily characterized by alveolar hemorrhage, thickening of the alveolar septa, intraalveolar accumulation of hemosiderin-containing macrophages, and nodular pulmonary remodeling. Thus, our model uncovers multiple consequences of BTC over-expression in vivo. These transgenic mice provide a useful model for examining the effects of BTC excess on different organs.