Regulation of organogenesis and hematopoiesis in development

我们之前报道过，缺乏rae28基因（一种与果蝇多栉群（PcG）基因同源的小鼠）的小鼠表现出骨骼的后向转变，包括神经嵴衍生组织缺陷和造血疾病在内的异常（Takihara等人，Development, 124, 3673- 82,1997）。在本研究中，我们研究了rae28缺陷胚胎心脏异常发育的分子机制，发现同源盒基因Nkx2.5的表达在胚胎9.5天（E9.5）的胚胎心脏中显着降低，而它通常是启动的。采用原位杂交技术检测了rae28缺陷胚近轴中胚层、后脑和咽弓34个Hox基因的表达。除Hoxb3和Hoxb4外，其余12个Hox基因在野生型胚胎后脑和咽弓中的表达模式均不受影响。Hoxb3异位表达从E10.5开始出现在后脑，从E9.5开始出现在咽弓。这些结果和神经嵴标志物p75的表达模式表明，神经嵴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，后脑异位表达的前边界逐渐向吻侧方向延伸。我们还检查了突变体在胚胎和新生儿阶段的造血系统。我们的研究结果表明，含有RAE28的PcG复合物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基因产物形成复合物，如M33、bmil和mel18。这些结果表明，在rae28缺陷小鼠中存在的PcG复合物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.