The role of Hand genes for the cardiac ventricular developinent and regionalization

手基因在心室发育和区域化中的作用

• 批准号: 18591168
• 负责人: MAEDA Jun
• 金额: $ 2.57万
• 依托单位: Keio University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591168/
• 关键词: Hand genes; ventricular chamber development; Pharyngeal arch development

Hand genes (Hand1/eHand and Hand2/dHand) encode critical transcription factors required for cardiovascular and pharyngeal development. Hand2 is expressed predominantly in developing right ventricle, whereas Hand1 is restricted in left ventricle. Both Hand genes direct overlapping expression in pharyngeal arch mesenchyme. Hand1 null cardiac-specific null mice display defects in left ventricle and endocardial cushion. Hand2 null (Hand2^<-/->) mice display severe hypoplasia of right ventricle and die at embryonic day (E) 10.5 due to the heart failure resulting in degenerative pharyngeal arch and limb buds. To delineate the genetic redundancy and regional function of Hand genes in murine development we genetically engineered Hand2^<Hand1/Hand1> mice where Hand2 gene was replaced by the Hand1 cDNA using homologous recombination so that Hand1 was driven under control of endogenous Hand2 promoter. We also generated Hand2^<Hand1/-> mice from mating of Hand2^<Hand1/+> mice with Hand2^<+/-> mice. Our observation reveled that Hand2^<Hand1/Hand1>mice had hypoplastic right ventricle and preserved pharyngeal arch and survived until E13.5. This phenotype was milder than that of Hand2^<-/->or Hand2^<Hand1/-> mice. These findings suggest that Hand1 could partially compensate the function of Hand2 in ventricular and pharyngeal arch formations in a dose dependent fashion during development. These results indicate that in mammalian cardiac ventricles and pharyngeal arch, Hand genes may have common function and partial genetic redundancy. The complementally expression of Hand genes may be essential for regionalization of right and left ventricles.

Hand基因（Hand 1/eHand和Hand 2/dHand）编码心血管和咽部发育所需的关键转录因子。Hand 2主要在发育中的右心室表达，而Hand 1仅在左心室表达。两个Hand基因在咽弓间充质中直接重叠表达。Hand 1 null心脏特异性null小鼠显示左心室和内膜垫缺陷。Hand 2缺失（Hand 2 ^<-/->）小鼠表现出严重的右心室发育不全，并在胚胎第（E）10.5天死于心力衰竭，导致退化的咽弓和肢芽。为了描述Hand基因在鼠发育中的遗传冗余和区域功能，我们对Hand 2 ^<Hand 1/Hand 1>小鼠进行遗传工程改造，其中使用同源重组将Hand 2基因替换为Hand 1 cDNA，使得Hand 1在内源性Hand 2启动子的控制下驱动。我们还从Hand 2 ^<Hand 1/->小鼠与Hand 2 ^<+/->小鼠的交配中产生了Hand 2 ^<Hand 1/->小鼠。我们的观察结果显示，Hand 2 ^<Hand 1/Hand 1>小鼠右心室发育不良，咽弓保留，并存活至E13.5。该表型比Hand 2 ^<-/->或Hand 2 ^<Hand 1/->小鼠的表型温和。这些结果表明，在发育过程中，Hand 1可以以剂量依赖的方式部分补偿Hand 2在心室和咽弓形成中的功能。这些结果表明，在哺乳动物的心室和咽弓中，Hand基因可能具有共同的功能和部分的遗传冗余。Hand基因的互补表达可能是左右心室定位的关键。

项目成果

Redundant and tissue-specific roles of Hand genes in heart, limbs, and cranial development.

手基因在心脏、四肢和颅骨发育中的冗余和组织特异性作用。

• 发表时间: 2007
• 作者: Maeda J.Tsuchihashi T; Yamagishi C;Srivastava D;Yamagishi H.
• 通讯作者: Yamagishi H.

9 Hand genes in the mammalian heart chamber formation.Future Aspects of Medical Sciences and Education"Challenge of Integrated medical Sciences"2nd IREIIMS Open Symposium,

9 哺乳动物心室形成中的手基因。医学科学和教育的未来方面“综合医学科学的挑战”第二届IREIIMS公开研讨会，

• 发表时间: 2007
• 作者: Jun Maeda;Hiroyuki Yamagishi;Takatoshi Tsuchiahshi;Eric N Olson;Deepak Srivastava;Bernardo Nadal-Ginard;Kintomo Takakura
• 通讯作者: Kintomo Takakura

Chapter 9. Hand genes in the mammalian heart chamber formation. Future Aspects of Medical Sciences and Education 2nd IREIIMS Open Symposium

第9章哺乳动物心室形成中的手基因。

• 发表时间: 2007
• 期刊: International Research and Educational Institute for Integrated Medical Sciences (IREIIMS), p.29-31, Tokyo Women's Medical University
• 作者: Jun;Maeda;Hiroyuki;Yamagishi;Takatoshi;Tsuchihashi;Eric N;Olson;Deepak;Srivastava;Nadal-Ginard;Bernardo;Kintomo;Takakura
• 通讯作者: Takakura

Hand genes in the mammalian heart formation

哺乳动物心脏形成中的手基因

• 发表时间: 2007
• 作者: Jun;Maeda;Takatoshi;Tsuchihashi;Hiroyuki;Yamagishi;Eric N;Olson;Deepak;Srivastava
• 通讯作者: Srivastava

III-K.循環器疾患/先天性心疾患心室中隔欠損症講義録 小児科学

III-K. 心血管疾病/先天性心脏病心室间隔缺损讲座记录儿科

• 发表时间: 2008
• 作者: 前田 潤;佐地 勉;有阪 治;大澤 真木子;近藤 直美;竹村 司
• 通讯作者: 竹村 司