Xu Jue, Chen Meiling, Yan Yanan, Zhao Qiaoxue, Shao Meiying, Huang Zhen
West China School of Public Health and Department of Stomatology, West China Fourth Hospital, Sichuan University, Chengdu, China.
Southern Center for Biomedical Research and Fujian Key Laboratory of Developmental and Neuro Biology, College of Life Sciences, Fujian Normal University, Fuzhou, China.
Int J Oral Sci. 2021 Nov 29;13(1):40. doi: 10.1038/s41368-021-00142-4.
The first branchial arch (BA1), which is derived from cranial neural crest (CNC) cells, gives rise to various orofacial tissues. Cre mice are widely used for the determination of CNC and exploration of gene functions in orofacial development. However, there is a lack of Cre mice specifically marked BA1's cells. Pax2-Cre allele was previously generated and has been widely used in the field of inner ear development. Here, by compounding Pax2-Cre and R26R-mTmG mice, we found a specific expression pattern of Pax2 cells that marked BA1's mesenchymal cells and the BA1-derivatives. Compared to Pax2-Cre; R26R-mTmG allele, GFP cells were abundantly found both in BA1 and second branchial arch in Wnt1-Cre;R26R-mTmG mice. As BMP4 signaling is required for orofacial development, we over-activated Bmp4 by using Pax2-Cre; pMes-BMP4 strain. Interestingly, our results showed bilateral hyperplasia between the upper and lower teeth. We also compare the phenotypes of Wnt1-Cre; pMes-BMP4 and Pax2-Cre; pMes-BMP4 strains and found severe deformation of molar buds, palate, and maxilla-mandibular bony structures in Wnt1-Cre; pMes-BMP4 mice; however, the morphology of these orofacial organs were comparable between controls and Pax2-Cre; pMes-BMP4 mice except for bilateral hyperplastic tissues. We further explore the properties of the hyperplastic tissue and found it is not derived from Runx2 cells but expresses Msx1, and probably caused by abnormal cell proliferation and altered expression pattern of p-Smad1/5/8. In sum, our findings suggest altering BMP4 signaling in BA1-specific cell lineage may lead to unique phenotypes in orofacial regions, further hinting that Pax2-Cre mice could be a new model for genetic manipulation of BA1-derived organogenesis in the orofacial region.
第一鳃弓（BA1）源自颅神经嵴（CNC）细胞，可产生多种口面部组织。Cre小鼠被广泛用于确定CNC以及探索口面部发育中的基因功能。然而，缺乏专门标记BA1细胞的Cre小鼠。Pax2-Cre等位基因先前已产生，并已在内耳发育领域广泛应用。在此，通过将Pax2-Cre和R26R-mTmG小鼠杂交，我们发现了Pax2细胞的一种特定表达模式，该模式标记了BA1的间充质细胞和BA1衍生细胞。与Pax2-Cre;R26R-mTmG等位基因相比，在Wnt1-Cre;R26R-mTmG小鼠的BA1和第二鳃弓中均大量发现了绿色荧光蛋白（GFP）细胞。由于口面部发育需要骨形态发生蛋白4（BMP4）信号传导，我们通过使用Pax2-Cre;pMes-BMP4品系过度激活Bmp4。有趣的是，我们的结果显示上下牙齿之间出现双侧增生。我们还比较了Wnt1-Cre;pMes-BMP4和Pax2-Cre;pMes-BMP4品系的表型，发现Wnt1-Cre;pMes-BMP4小鼠的磨牙芽、腭和上颌-下颌骨结构出现严重变形；然而，除了双侧增生组织外，对照小鼠和Pax2-Cre;pMes-BMP4小鼠的这些口面部器官形态相当。我们进一步探究了增生组织的特性，发现它并非源自Runx2细胞，而是表达Msx1，并且可能是由异常细胞增殖和p-Smad1/5/8表达模式改变所致。总之，我们的研究结果表明，改变BA1特异性细胞谱系中的BMP4信号传导可能导致口面部区域出现独特表型，进一步暗示Pax2-Cre小鼠可能成为口面部区域BA1衍生器官发生基因操作的新模型。
