Wt1 and β-catenin cooperatively regulate diaphragm development in the mouse
Wt1 and β-catenin cooperatively regulate diaphragm development in the mouse
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DOI：
10.1016/j.ydbio.2015.08.009
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发表时间：
2015-11-01
影响因子：
2.7
通讯作者：
Ackerman, Kate G.
中科院分区：
文献类型：
--
作者：
Paris, Nicole D.;Coles, Garry L.;Ackerman, Kate G.
发育中的横膈膜由各种分化细胞类型组成，其中许多细胞在器官发生过程中没有得到很好的表征。一种重要但尚未完全了解的组织，即间皮细胞，在发育的早期阶段就明显存在。先天性膈疝（CDH）发生在人类，当隔膜组织在发育过程中丢失时，导致出生后的高发病率和死亡率。我们利用Wilms Tumor 1（Wt 1）突变小鼠模型来研究间皮细胞在正常膈肌信号传导和发育中的参与。此外，在发现经典Wnt信号传导和β-连环蛋白在WO突变间皮中减少后，我们开发并表征了Wt 1（CreERT 2）驱动的CDH β-连环蛋白功能丧失模型。只有在E10.5和E11.5之间注射他莫昔芬时，Wt 1谱系中诱导的β-连环蛋白丢失或组成性激活的小鼠才会受到影响，这揭示了Wt 1/β-连环蛋白活性的关键时间范围。条件性β-连环蛋白缺失表型模仿Wt 1突变型隔膜缺陷，而Wt 1突变型背景下β-连环蛋白的组成性激活足以关闭隔膜缺陷。增殖和凋亡受到影响，但主要是这些基因操作似乎导致正常的膈肌分化的变化。我们的数据表明间皮细胞信号传导在隔膜的正确形成中起着重要作用。(C)2015 Elsevier Inc. All rights reserved.
The developing diaphragm consists of various differentiating cell types, many of which are not well characterized during organogenesis. One important but incompletely understood tissue, the diaphragmatic mesothelium, is distinctively present from early stages of development. Congenital Diaphragmatic Hernia (CDH) occurs in humans when diaphragm tissue is lost during development, resulting in high morbidity and mortality postnatally. We utilized a Wilms Tumor 1 (Wt1) mutant mouse model to investigate the involvement of the mesothelium in normal diaphragm signaling and development. Additionally, we developed and characterized a Wt1(CreERT2)-driven beta-catenin loss-of-function model of CDH after finding that canonical Wnt signaling and beta-catenin are reduced in WO mutant mesothelium. Mice with beta-catenin loss or constitutive activation induced in the Wt1 lineage are only affected when tamoxifen injection occurs between E10.5 and E11.5, revealing a critical time-frame for Wt1/ beta-catenin activity. Conditional beta-catenin loss phenocopies the Wt1 mutant diaphragm defect, while constitutive activation of beta-catenin on the Wt1 mutant background is sufficient to close the diaphragm defect. Proliferation and apoptosis are affected, but primarily these genetic manipulations appear to lead to a change in normal diaphragm differentiation. Our data suggest a fundamental role for mesothelial signaling in proper formation of the diaphragm. (C) 2015 Elsevier Inc. All rights reserved.