Yu B D, Hanson R D, Hess J L, Horning S E, Korsmeyer S J
Howard Hughes Medical Institute, Division of Molecular Oncology, Departments of Medicine and Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10632-6. doi: 10.1073/pnas.95.18.10632.
Determinative events in vertebrate embryogenesis appear to require the continuous expression of spatial regulators such as the clustered homeobox genes. The mechanisms that govern long-term patterns of gene expression are not well understood. In Drosophila, active and silent states of developmentally regulated loci are maintained by trithorax and Polycomb group. We have examined the developmental role of a mammalian homolog of trx and putative oncogene, Mll. Knockout mice reveal that Mll is required for maintenance of gene expression early in embryogenesis. Downstream targets of Mll including Hoxa7 are activated appropriately in the absence of Mll but require Mll for sustaining their expression. The Mll-/- phenotype manifests later in development and is characterized by branchial arch dysplasia and aberrant segmental boundaries of spinal ganglia and somites. Thus, Mll represents an essential mechanism of transcriptional maintenance in mammalian development, which functions in multiple morphogenetic processes.
脊椎动物胚胎发育中的决定性事件似乎需要空间调节因子的持续表达，如成簇的同源框基因。控制基因长期表达模式的机制尚未完全了解。在果蝇中，发育调控位点的活跃和沉默状态由三胸复合物和多梳蛋白复合物维持。我们研究了三胸复合物的哺乳动物同源物及假定的癌基因Mll的发育作用。基因敲除小鼠显示，Mll是胚胎发育早期基因表达维持所必需的。Mll的下游靶标包括Hoxa7，在没有Mll的情况下能被适当激活，但维持其表达需要Mll。Mll基因敲除小鼠的表型在发育后期出现，其特征为鳃弓发育异常以及脊髓神经节和体节的节段边界异常。因此，Mll代表了哺乳动物发育中转录维持的一种基本机制，它在多个形态发生过程中发挥作用。
