Study of CATCH22 syndorme using disease model mice

在我们以前的研究中，我们报道了rae 28基因缺陷的小鼠，该基因是果蝇多梳组（PcG）基因的小鼠同源物，除了骨骼的后部转化外，还显示出包括神经嵴衍生组织缺陷的异常（Takihara等人，Development，124，3673-82，1997）。在本研究中，我们研究了rae 28缺陷胚胎心脏发育异常的分子机制，发现同源异型盒基因Nkx2.5的表达在胚胎第9.5天（E9.5）的心脏中显着减少，而正常启动。我们还研究了34个Hox基因的表达在近轴中胚层，后脑和咽弓的rae 28缺陷的胚胎通过原位杂交。除Hoxb 3和Hoxb 4外，野生型胚胎后脑和咽弓中表达的所有12个Hox基因的表达模式均不受影响。Hoxb 3的异位表达从E10.5开始在后脑中观察到，并且从E9.5开始在咽弓中观察到。这些结果和神经嵴标记物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Hoxb 3。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。我们发现rae 28基因产物与其他PcG基因产物如M33、bmil和mel 18形成复合物。这些结果表明存在于rae 28缺陷小鼠中的PcG复合物不能稳定地固定和维持Hoxb 3表达模式。

In our previous study, we reported that mice deficient for the rae28 gene, a mouse homologue of the Drosophila polycomb group (PcG) of genes, show anomalies including defects of the neural crest derived tissues, in addition to the posterior transformation of skeletons (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. We also examined the expression of 34 Hox genes in paraxial mesoderm, hindbrain and pharyngeal arches of the rae28-deficient embryos 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 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.