骨形态发生蛋白I型受体抑制诱导小鼠腭裂伴小颌畸形和下唇裂

Q Medicine Birth defects research. Part A, Clinical and molecular teratology Pub Date : 2016-05-06 DOI:10.1002/bdra.23504

Yongzhen Lai, Changfu Xie, Shixian Zhang, Guowu Gan, Di Wu, Weihui Chen

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引用次数: 6

摘要

研究表明，胚胎发育过程中骨形态发生蛋白(BMP)信号的变化可导致包括腭裂在内的颅面畸形。BMP信号是否能在药理学上影响颅面形态发生尚不确定。方法从胚胎第10.5天(E10.5)至E15.5天，连续2次腹腔注射BMP I型受体抑制剂LDN-193189，剂量分别为3、6、9 mg/kg。在E16.5时，对胚胎进行面部测量分析和组织学研究，以确定畸形的最佳浓度。随后的胚胎表型通过组织学，全支架骨骼染色，显微计算机断层扫描和腭有机培养进行详细分析。我们进一步使用免疫组织化学分析bmp介导的典型和非典型信号成分的蛋白表达。结果确定LDN-193189的最佳浓度为6 mg/kg。在子宫内，LDN-193189暴露导致前腭部分裂或完全裂，其原因是次腭细胞增殖率降低，以及小颌畸形导致的腭抬高延迟。对E12.5和E13.5腭架信号转导的分析发现，LDN-193189治疗后，BMP/Smad信号(p-Smad1/5/8)显著减少，BMP非规范信号(p-p38, p-Erk1/2)保持不变。结论LDN-193189可通过选择性靶向BMP/Smad信号通路调控BMP信号通路，影响腭部形态发生，产生与基因突变相似的表型。本工作建立了一种新的致畸性腭裂小鼠模型。出生缺陷研究(A辑)(6):612 - 623,2016。©2016 Wiley期刊公司

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Bone morphogenetic protein type I receptor inhibition induces cleft palate associated with micrognathia and cleft lower lip in mice

Background

Gain-of- and loss-of-function studies have demonstrated that changes in bone morphogenetic protein (BMP) signaling during embryo development cause craniofacial malformations, including cleft palate. It remains uncertain whether BMP signaling could be targeted pharmacologically to affect craniofacial morphogenesis.

Methods

Pregnant C57Bl/6J mice were treated with the BMP type I receptor inhibitor LDN-193189 at the dose of 3, 6, or 9 mg/kg twice a day by intraperitoneal injection from embryonic day 10.5 (E10.5) to E15.5. At E16.5, embryos were investigated by facial measurement analysis and histology to determine the optimal concentration for malformation. Subsequent embryonic phenotypes were analyzed in detail by histology, whole-mount skeletal staining, micro-computed tomography, and palatal organic culture. We further used immunohistochemistry to analyze protein expression of the BMP-mediated canonical and noncanonical signaling components.

Results

The optimal concentration of LDN-193189 was determined to be 6 mg/kg. In utero, LDN-193189 exposures induced partial clefting of the anterior palate or complete cleft palate, which was attributed to a reduced cell proliferation rate in the secondary palate, and delayed palatal elevation caused by micrognathia. Analysis of signal transduction in palatal shelves at E12.5 and E13.5 identified a significant reduction of BMP/Smad signaling (p-Smad1/5/8) and unchanged BMP noncanonical signaling (p-p38, p-Erk1/2) after treatment with LDN-193189.

Conclusion

The results of this study indicate that LDN-193189 can be used to manipulate BMP signaling by selectively targeting the BMP/Smad signaling pathway to affect palatal morphogenesis and produce phenotypes mimicking those caused by genetic mutations. This work established a novel mouse model for teratogen-induced cleft palate. Birth Defects Research (Part A) 106:612–623, 2016. © 2016 Wiley Periodicals, Inc.

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