Stowers Institute for Medical Research, Kansas City, MO, 64110, USA.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
Nat Commun. 2019 Mar 13;10(1):1189. doi: 10.1038/s41467-019-09197-8.
In jawed vertebrates (gnathostomes), Hox genes play an important role in patterning head and jaw formation, but mechanisms coupling Hox genes to neural crest (NC) are unknown. Here we use cross-species regulatory comparisons between gnathostomes and lamprey, a jawless extant vertebrate, to investigate conserved ancestral mechanisms regulating Hox2 genes in NC. Gnathostome Hoxa2 and Hoxb2 NC enhancers mediate equivalent NC expression in lamprey and gnathostomes, revealing ancient conservation of Hox upstream regulatory components in NC. In characterizing a lamprey hoxα2 NC/hindbrain enhancer, we identify essential Meis, Pbx, and Hox binding sites that are functionally conserved within Hoxa2/Hoxb2 NC enhancers. This suggests that the lamprey hoxα2 enhancer retains ancestral activity and that Hoxa2/Hoxb2 NC enhancers are ancient paralogues, which diverged in hindbrain and NC activities. This identifies an ancestral mechanism for Hox2 NC regulation involving a Hox-TALE regulatory circuit, potentiated by inputs from Meis and Pbx proteins and Hox auto-/cross-regulatory interactions.
在有颌脊椎动物（颌口类）中，Hox 基因在头部和颌骨形成的模式形成中起着重要作用，但将 Hox 基因与神经嵴（NC）偶联的机制尚不清楚。在这里，我们使用颌口类和无颌现存脊椎动物七鳃鳗之间的跨物种调控比较，研究调控 NC 中 Hox2 基因的保守祖先机制。颌口类 Hoxa2 和 Hoxb2 的 NC 增强子在七鳃鳗和颌口类中介导等效的 NC 表达，揭示了 NC 中 Hox 上游调控成分的古老保守性。在对七鳃鳗 hoxα2 NC/后脑增强子进行表征时，我们鉴定了必需的 Meis、Pbx 和 Hox 结合位点，这些位点在 Hoxa2/Hoxb2 的 NC 增强子中具有功能保守性。这表明，七鳃鳗 hoxα2 增强子保留了祖先的活性，而 Hoxa2/Hoxb2 的 NC 增强子是古老的同源物，它们在后脑和 NC 活性上发生了分化。这确定了涉及 Hox-TALE 调控回路的 Hox2 NC 调控的祖先机制，该机制由 Meis 和 Pbx 蛋白以及 Hox 自/交叉调控相互作用的输入增强。
