Twist1 Acts Upstream of the Dlx5-Hand2 Pathway to Pattern the Mammalian Jaw

IF 5.7 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE Journal of Dental Research Pub Date : 2024-12-21 DOI:10.1177/00220345241291527
N. Adhikari, Z. Wu, Y. Huang, Y. Lan, R. Jiang
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Abstract

Both the upper and lower jaws develop from cranial neural crest cells (CNCCs) populating the first pharyngeal arch in all gnathostomes. Previous studies showed that the Edn1/Ednra-Dlx5/Dlx6-Hand2 signaling pathway is necessary for lower jaw formation and that ectopic expression of Edn1 or Hand2 throughout the CNCCs partly transformed the upper jaw to lower jaw structures, but the molecular mechanisms regulating upper jaw development remain unclear. Here we show that the basic helix-loop-helix transcription factor Twist1 is required for upper jaw development. Whereas the Twist1fl/fl; Wnt1-Cre mouse embryos, with tissue-specific inactivation of Twist1 in premigratory CNCCs, exhibited aberrantly persistent expression of the key neuroglial lineage regulator Sox10 in the postmigratory CNCCs populating the facial primordia, we found that genetic inactivation of Sox10 did not rescue the defects in CNCC survival and patterning in Twist1fl/fl; Wnt1-Cre embryos. However, analysis of Sox10fl/+; Twist1fl/fl; Wnt1-Cre mice revealed duplicated mandibular structures, including ectopic Meckel’s cartilage, in place of the maxilla. Both Sox10fl/+; Twist1fl/fl; Wnt1-Cre and Sox10fl/fl; Twist1fl/fl; Wnt1-Cre embryos exhibited ectopic expression of Dlx5 and Hand2 in the developing maxillary processes at E10.5. Furthermore, we found that Twist1fl/fl; Wnt1-Cre embryos also expressed Dlx5 and Hand2 ectopically in the maxillary domain at E10.5 and subsequently developed Meckel’s cartilage–like cartilage rods bilaterally at the maxillary region. However, the expression of Edn1 was unaltered in the developing Twist1fl/fl; Wnt1-Cre embryos, indicating that Twist1 functions in the CNCC-derived facial mesenchyme to regulate the Dlx5-Hand2 pathway without affecting Edn1 expression in the epithelial and mesodermal compartments. We further show that Twist1 represses reporter gene activation driven by the Dlx5/Dlx6 intergenic enhancer known to drive Dlx5/Dlx6 expression in the developing mandibular arch. Together, these data identify a new role of Twist1 in patterning the regional identities of the CNCC-derived facial mesenchyme and provide novel insight into the pathogenic mechanisms underlying TWIST1-related craniofacial developmental disorders.
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Twist1在Dlx5-Hand2通路上游作用,决定哺乳动物下颚的模式
上颚和下颚都是由头神经嵴细胞(cncc)发育而来,这些细胞生长在所有颌口的第一咽弓上。先前的研究表明,Edn1/Ednra-Dlx5/Dlx6-Hand2信号通路是下颌形成所必需的,Edn1或Hand2在cncc中的异位表达部分地将上颌结构转化为下颌结构,但调节上颌发育的分子机制尚不清楚。在这里,我们表明基本的螺旋-环-螺旋转录因子Twist1是上颌发育所必需的。而Twist1fl/fl;Wnt1-Cre小鼠胚胎在迁移前CNCC中组织特异性失活,在迁移后填充面部原基的CNCC中表现出关键神经胶质谱系调节因子Sox10的异常持续表达,我们发现Sox10的遗传失活并不能挽救CNCC存活和Twist1fl/fl模式的缺陷;Wnt1-Cre胚胎。然而,分析Sox10fl/+;Twist1fl / fl;Wnt1-Cre小鼠显示了重复的下颌骨结构,包括异位的梅克尔软骨,取代了上颌骨。Sox10fl / +;Twist1fl / fl;Wnt1-Cre和Sox10fl/fl;Twist1fl / fl;Wnt1-Cre胚胎在E10.5发育的上颌突中表现出Dlx5和Hand2的异位表达。此外,我们发现Twist1fl/fl;Wnt1-Cre胚胎在E10.5时也在上颌区域异位表达Dlx5和Hand2,随后在上颌区域双侧发育出Meckel软骨样软骨棒。而在发育中的Twist1fl/fl中,Edn1的表达没有变化;Wnt1-Cre胚胎,表明Twist1在cncc来源的面间质中发挥作用,调节Dlx5-Hand2通路,而不影响上皮和中胚层室中Edn1的表达。我们进一步表明,Twist1抑制由Dlx5/Dlx6基因间增强子驱动的报告基因激活,已知该增强子在发育中的下颌弓中驱动Dlx5/Dlx6表达。总之,这些数据确定了Twist1在cncc衍生的面部间质区域特征中的新作用,并为Twist1相关颅面发育障碍的致病机制提供了新的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Dental Research
Journal of Dental Research 医学-牙科与口腔外科
CiteScore
15.30
自引率
3.90%
发文量
155
审稿时长
3-8 weeks
期刊介绍: The Journal of Dental Research (JDR) is a peer-reviewed scientific journal committed to sharing new knowledge and information on all sciences related to dentistry and the oral cavity, covering health and disease. With monthly publications, JDR ensures timely communication of the latest research to the oral and dental community.
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