Msx1 is essential for proper rostral tip formation of the mouse mandible
Msx1 is essential for proper rostral tip formation of the mouse mandible
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Msx1 对于小鼠下颌骨的正确嘴尖形成至关重要
DOI：
10.1016/j.bbrc.2022.12.047
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发表时间：
2023
影响因子：
3.1
通讯作者：
Kawamoto Tatsuo
中科院分区：
文献类型：
--
作者：
Shibuya Saori;Nakatomi Mitsushiro;Kometani-Gunjigake Kaori;Nakao-Kuroishi Kayoko;Matsuyama Kae;Kataoka Shinji;Toyono Takashi;Seta Yuji;Kawamoto Tatsuo
在下颌发育过程中，起源于第一鳃弓的左右下颌突向中线生长并融合，形成下颌骨的嘴尖区。在这一过程中，严重和轻微的失败分别导致罕见的下唇正中裂和下巴裂。下颌尖形成的详细分子机制尚不清楚。我们推测Msx1基因参与了下颌尖端的发育，因为Msx1基因在其他颅面形态发生过程中起着中心作用，如牙齿和二次腭部发育。Msx1在发育中的下颌骨喙端有正常表达，但在下颌尖软组织中的表达低于下颌切牙蕾下部。对照组和Msx1基因缺失(Msx1-−/−)小鼠左右下颌突的吻端在胚胎第12.5天未融合，而对照组在胚胎13.5天观察到这些突起的完全融合。在对照中，融合的突起呈圆锥形，而在Msx1−/−中，相同的区域保持分叉。这种表型以100%的外显率出现，在随后的发育阶段不会恢复。此外，从E14.5开始，Msx1−/−中除轮廓表面软组织外，Meckel‘s软骨也是未融合和分叉的。骨形态发生蛋白(BMP)信号转导因子Phosho-Smad1/5在E12.5和E13.5的Msx1−/−中表达下调，可能是由于Bmp4在邻近下切牙牙芽中表达下调所致。在同一发育阶段，Msx1−/−的下颌尖部中线区域的细胞增殖显著降低，同时观察到pSmad的下调。我们的结果表明，Msx1对于正常的下颌尖发育是不可或缺的。
The right and left mandibular processes derived from the first branchial arch grow toward the midline and fuse to create the rostral tip region of the mandible during mandibular development. Severe and mild cases of failure in this process results in rare median cleft of the lower lip and cleft chin, respectively. The detailed molecular mechanisms of mandibular tip formation are unknown. We hypothesize that theMsx1gene is involved in mandibular tip development, becauseMsx1has a central role in other craniofacial morphogenesis processes, such as teeth and the secondary palate development. NormalMsx1expression was observed in the rostral end of the developing mandible; however, a reduced expression ofMsx1was observed in the soft tissue of the mandibular tip than in the lower incisor bud region. The rostral tip of the right and left mandibular processes was unfused in both control andMsx1-null (Msx1−/−) mice at embryonic day (E) 12.5; however, a complete fusion of these processes was observed at E13.5 in the control. The fused processes exhibited a conical shape in the control, whereas the same region remained bifurcated inMsx1−/−. This phenotype occurred with 100% penetrance and was not restored at subsequent stages of development. Furthermore, Meckel's cartilage in addition to the outline surface soft tissues was also unfused and bifurcated inMsx1−/−from E14.5 onward. The expression of phosho-Smad1/5, which is a mediator of bone morphogenetic protein (Bmp) signaling, was downregulated in the mandibular tip ofMsx1−/−at E12.5 and E13.5, probably due to the downregulated Bmp4 expression in the neighboring lower incisor bud. Cell proliferation was significantly reduced in the midline region of the mandibular tip inMsx1−/−at the same developmental stages in which downregulation of pSmad was observed. Our results indicate thatMsx1is indispensable for proper mandibular tip development.