Mesenchymal Wnt signaling promotes formation of sternum and thoracic body wall.
Mesenchymal Wnt signaling promotes formation of sternum and thoracic body wall.
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DOI：
10.1016/j.ydbio.2015.02.014
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发表时间：
2015-05-15
影响因子：
2.7
通讯作者：
Sinner, Debora
中科院分区：
文献类型：
--
作者：
Snowball, John;Ambalavanan, Manoj;Cornett, Bridget;Lang, Richard;Whitsett, Jeffrey;Sinner, Debora
中线缺陷约占出生时观察到的先天性异常的5%。然而，腹侧体壁形成的分子机制还不是很清楚。最近的研究将豪猪-一种介导Wnt配体酰化的O-乙酰转移酶的突变与胸壁缺陷联系在一起。我们推测Wnt信号异常参与了胸壁闭合缺陷的发病机制。我们建立了一个小鼠模型，其中编码介导Wnt配体分泌的Cargo受体的Wls(WLS)从使用Dermo1Cre小鼠的发育中的间充质中有条件地删除。胚胎在妊娠中期死亡。在E13.5，在前肢、颌骨和肋骨笼中观察到骨骼缺陷。E14.5，胸骨中线缺陷开始出现：胸骨融合失败，心脏在中线(心脏异位)从体壁突出。为了确定在Wlsf/f；Dermo1Cre/+胚胎中观察到的表型背后的分子机制，我们利用Axin2LacZ和BatGal报告小鼠测试了Wnt/β-catenin信号在胚胎腹侧体壁发育中是否起作用。在胸骨融合前，Wnt/β-catenin信号在腹侧体壁的中线处被观察到，而在WLS的间质缺失后，这种活动模式被改变并散布于整个体壁。Wlsf/f；Dermo1Cre/+胸壁的间充质细胞迁移被破坏，部分原因是体外检测的异常的非规范Wnt信号。在间充质中介导Wnt/β-catenin信号转导的LRP5和LRP6受体的缺失，部分概括了Wlsf/f胸中线观察到的表型；Demo1Cre/+胚胎支持Wnt/β-catenin信号活性在腹侧体壁间充质正常形成中的作用。我们的结论是，WLS介导的Wnt配体从发育中的腹侧体壁间充质中分泌出来，在胸骨融合和次级体壁的关闭中起着关键作用。因此，腹侧体壁间充质中WLS活性受损是导致心脏异位和胸骨不融合的机制之一。
Midline defects account for approximately 5% of congenital abnormalities observed at birth. However, the molecular mechanisms underlying the formation of the ventral body wall are not well understood. Recent studies linked mutations in Porcupine—an O-acetyl transferase mediating Wnt ligand acylation—with defects in the thoracic body wall. We hypothesized that anomalous Wnt signaling is involved in the pathogenesis of defective closure of the thoracic body wall. We generated a mouse model wherein Wntless (Wls), which encodes a cargo receptor mediating secretion of Wnt ligands, was conditionally deleted from the developing mesenchyme using Dermo1Cre mice. Wlsf/f;Dermo1Cre/+ embryos died during mid-gestation. At E13.5, skeletal defects were observed in the forelimbs, jaw, and rib cage. At E14.5, midline defects in the thoracic body wall began to emerge: the sternum failed to fuse and the heart protruded through the body wall at the midline (ectopia cordis). To determine the molecular mechanism underlying the phenotype observed in Wlsf/f;Dermo1Cre/+ embryos, we tested whether Wnt/β-catenin signaling was operative in developing the embryonic ventral body wall using Axin2LacZ and BatGal reporter mice. While Wnt/β-catenin signaling activity was observed at the midline of the ventral body wall before sternal fusion, this pattern of activity was altered and scattered throughout the body wall after mesenchymal deletion of Wls. Mesenchymal cell migration was disrupted in Wlsf/f;Dermo1Cre/+ thoracic body wall partially due to anomalous non-canonical Wnt signaling as determined by in vitro assays. Deletion of Lrp5 and Lrp6 receptors, which mediate Wnt/β-catenin signaling in the mesenchyme, partially recapitulated the phenotype observed in the chest midline of Wlsf/f;Dermo1Cre/+ embryos supporting a role for Wnt/β-catenin signaling activity in the normal formation of the ventral body wall mesenchyme. We conclude that Wls-mediated secretion of Wnt ligands from the developing ventral body wall mesenchyme plays a critical role in fusion of the sternum and closure of the secondary body wall. Thus, impaired Wls activity in the ventral body wall mesenchyme is a mechanism underlying ectopia cordis and unfused sternum.
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影响因子：
2.7
作者：
Cornett, Bridget;Snowball, John;Varisco, Brian M.;Lang, Richard;Whitsett, Jeffrey;Sinner, Debora
通讯作者：
Sinner, Debora
影响因子：
2.7
作者：
Joeng KS;Schumacher CA;Zylstra-Diegel CR;Long F;Williams BO
通讯作者：
Williams BO
影响因子：
4
作者：
Maas, S. M.;Lombardi, M. P.;Hennekam, Raoul C. M.
通讯作者：
Hennekam, Raoul C. M.
影响因子：
5.3
作者：
Lustig, B;Jerchow, B;Behrens, J
通讯作者：
Behrens, J
影响因子：
2.7
作者：
Herr, Patrick;Basler, Konrad
通讯作者：
Basler, Konrad