Division in Anatomy and Developmental Biology, Department of Oral Biology, Oral Science Research Center, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, South Korea.
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
Dev Dyn. 2019 Dec;248(12):1264-1272. doi: 10.1002/dvdy.109. Epub 2019 Sep 16.
Six1 is a transcriptional factor that plays an important role in embryonic development. Mouse and chick embryos deficient for Six1 have multiple craniofacial anomalies in the facial bones and cartilages. Multiple Six1 enhancers have been identified, but none of them has been reported to be active in the maxillary and mandibular process.
We studied two Six1 enhancers in the chick neural crest tissues during craniofacial development. We showed that two evolutionarily conserved enhancers, Six1E1 and Six1E2, act synergistically. Neither Six1E1 nor Six1E2 alone can drive enhancer reporter signal in the maxillary or mandibular processes. However, their combination, Six1E, showed robust enhancer activity in these tissues. Similar reporter signal can also be driven by the mouse homolog of Six1E. Mutations of multiple conserved transcriptional factor binding sites altered the enhancer activity of Six1E, especially mutation of the LIM homeobox binding site, dramatically reduced the enhancer activity, implying that the Lhx protein family be an important regulator of Six1 expression.
This study, for the first time, described the synergistic activation of two Six1 enhancers in the maxillary and mandibular processes and will facilitate more detailed studies of the regulation of Six1 in craniofacial development.
Six1 是一种转录因子，在胚胎发育中发挥重要作用。缺乏 Six1 的小鼠和鸡胚在面部骨骼和软骨中具有多种颅面异常。已经鉴定出多个 Six1 增强子，但没有一个被报道在上颌和下颌突中具有活性。
我们在颅面发育过程中研究了鸡神经嵴组织中的两个 Six1 增强子。我们表明，两个进化上保守的增强子 Six1E1 和 Six1E2 协同作用。单独的 Six1E1 或 Six1E2 均不能在上颌或下颌突中驱动增强子报告基因信号。然而，它们的组合 Six1E 在这些组织中显示出强大的增强子活性。类似的报告基因信号也可以由 Six1E 的小鼠同源物驱动。多个保守转录因子结合位点的突变改变了 Six1E 的增强子活性，特别是 LIM 同源盒结合位点的突变，大大降低了增强子活性，表明 Lhx 蛋白家族是 Six1 表达的重要调节剂。
这项研究首次描述了两个 Six1 增强子在上颌和下颌突中的协同激活，并将促进对 Six1 在颅面发育中的调控的更详细研究。
