Regulation of organogenesis and hematopoiesis in development

我们以前报道过，缺乏rae28基因的小鼠表现出骨骼的后部转化，异常包括神经脊衍生组织的缺陷和造血障碍(Takihara等，Development，124,3673-82,1997)。rae28基因是果蝇多梳基因(PcG)的小鼠同源基因。在本研究中，我们研究了RAE28缺陷胚胎心脏发育异常的分子机制，发现同源框基因NKX2.5在胚胎9.5天(E9.5天)的心脏中表达显著降低，而它正常启动。用原位杂交的方法检测了34个HOX基因在rae28基因缺陷胚胎的中胚层、后脑和咽弓中的表达。除HOXB3和HOXB4外，所有12个HOX基因在野生型胚胎的后脑和咽弓中的表达模式没有受到影响。从E10.5开始，Hoxb3在后脑中异位表达，从E9.5开始，在咽弓观察到异位表达。这些结果和神经脊标记p75的表达模式表明，神经脊细胞在离开后脑后开始异位表达Hoxb3。有趣的是，在发育过程中，后脑异位表达的前界逐渐向吻部方向延伸。我们还检测了突变体在胚胎和新生儿阶段的造血系统。我们的结果表明，含有RAE28的PcG复合体对于哺乳动物淋巴造血的正常发育和/或维持是必需的。我们发现rae28基因产物与其他PcG基因产物如M33、BmIL和Mel18形成复合体。这些结果表明，rae28缺陷小鼠体内存在的PcG复合体不能稳定地固定和维持Hoxb3的表达模式。

We reported previously that mice deficient for the rae28 gene, a mouse homologue of the Drosophila polycomb group (PcG) of genes, show the posterior transformation of skeletons, anomalies including defects of the neural crest derived tissues and hematopoietic disorders (Takihara et al., Development, 124, 3673-82, 1997). In the present study, we examined the molecular mechanisms underlying the abnormal cardiac development in the rae28-deficient embryos, and found that the expression of a homeobox gene Nkx2.5 is markedly reduced in the heart of embryos from embryonic day 9.5 (E9.5), while it is normally initiated. The expression of 34 Hox genes in paraxial mesoderm, hindbrain and pharyngeal arches of the rae28-deficient embryos was examined by in situ hybridization. Except for Hoxb3 and Hoxb4, the expression patterns of all 12 Hox genes expressed in the hindbrains and pharyngeal arches of the wild-type embryos are not affected. Ectopic expression of Hoxb3 was observed in the hindbrain from E10.5, and in the pharyngeal arch, from E9.5. These results and the expression patterns of a neural crest marker, p75, suggest that the neural crest cells begin to ectopically express Hoxb3 after leaving the hindbrain. Interestingly, the anterior boundary of ectopic expression in the hindbrain extends gradually in the rostral direction during development. We also examined the hematopoietic systems of the mutant in the embryonic and neonatal stages. Our results suggest that PcG complexes containing RAE28 is required for the proper development and/or maintenance of lymphohematopoiesis in mammals. We found that the rae28 gene product forms complexes with the products of other PcG genes, such as M33, bmil and mel18. These results indicate that the PcG complexes present in the rae28-deficient mice cannot stably fix and maintain Hoxb3 expression patterns.