Study of CATCH22 syndorme using disease model mice

CATCH22综合征疾病模型小鼠研究

• 批准号: 10470039
• 负责人: SHIMADA Kazunori
• 金额: $ 4.93万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470039/
• 关键词: disease model mice; knockout mouse; rae28 gene; Hox gene; Nkx2.5 gene; neural crest; CATCH22 syndorme; congenital heart disease; Hand1; ANF; ポリホメオティック遺伝子

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.

在我们之前的研究中，我们报道了缺乏 rae28 基因（果蝇多梳群 (PcG) 基因的小鼠同源物）的小鼠，除了骨骼后部变形外，还表现出包括神经嵴衍生组织缺陷在内的异常现象（Takihara等人，发展，124, 3673-82, 1997）。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的表达在胚胎第9.5天（E9.5）的胚胎心脏中显着降低。 ），而它通常是启动的。我们还通过原位杂交检测了 rae28 缺陷胚胎的轴旁中胚层、后脑和咽弓中 34 个 Hox 基因的表达。除Hoxb3和Hoxb4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。从E10.5开始在后脑中观察到Hoxb3的异位表达，从E9.5开始在咽弓中观察到Hoxb3的异位表达。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 Hoxb3。有趣的是，后脑异位表达的前边界在发育过程中逐渐向喙方向延伸。我们发现rae28基因产物与其他PcG基因的产物形成复合物，例如M33、bmil和mel18。这些结果表明存在于rae28缺陷小鼠中的PcG复合物不能稳定地固定和维持Hoxb3表达模式。

项目成果

Tomotsune,D.: "A novel member of murine Polycomb-group proteins, Sex comb on midleg homolog protein is highly conserved, and interacts with RAE28/mphl in vitro"Differentiation. 65. 229-239 (1999)

Tomotsune,D.：“鼠科多梳族蛋白的新成员，中腿同源蛋白上的性别梳高度保守，并在体外与 RAE28/mphl 相互作用”分化。

N. Hashimoto: "RAE28, BM11, and M33 Are Members of Heterogeneous Multimeric Mammalian Policomb Group Complexes"BIOCHEMICAL AND BIOPHYSICAL RESEACH COMMUNICATIONS. 245. 356-365 (1998)

N. Hashimoto：“RAE28、BM11 和 M33 是异质多聚哺乳动物 Policomb 群复合体的成员”生物化学和生物物理研究通讯。

Motaleb, Md. A.: "Characterization of cis-elements required for the transcriptional activation of the rae28/mphl gene in F9 cells"Biophys. Biochem. Res. Commun.. 262. 509-515 (1999)

Motaleb, Md. A.：“F9 细胞中 rae28/mphl 基因转录激活所需的顺式元件的表征”Biophys。

M. A. Motaleb: "Characterization of cis-elements required for the transcriptional activation of the rae28/mph1 gene in F9 cells"Biochem. Biophys. Res. Commun.. 262. 509-515 (1998)

M. A. Motaleb：“F9 细胞中 rae28/mph1 基因转录激活所需的顺式元件的表征”Biochem。

Ohta,H.: "Isolation and chromosomal localization of the HPHI gene, a human homologue of the polyhomeotic gene"DNA sequence. (発表予定).

Ohta, H.：“HPHI 基因（多同源基因的人类同源物）DNA 序列的分离和染色体定位”（待提交）。