| Project/Area Number |
21590221
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General anatomy (including Histology/Embryology)
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| Research Institution | Kitasato University |
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Principal Investigator |
KAMEDA Youko 北里大学, 医学部, 名誉教授 (10032898)
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| Co-Investigator(Kenkyū-buntansha) |
三浦 正明 北里大学, 医学部, 講師 (60276053)
新井 雄太 北里大学, 医学部, 講師 (60329026)
武田 啓 北里大学, 医学部, 講師 (20197297)
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| Co-Investigator(Renkei-kenkyūsha) |
SAITOH Takayoshi 北里大学, 大学院・理学研究科, 大学院生
AKIMOTO Minekatsu 北里大学, 大学院・医療系研究科, 大学院生
NEMOTO Noriko 北里大学, 医学部, 技術員
KATOH Tokio 北里大学, 医学部, 技術員
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2009: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | Hes1-/-マウス / Wnt1-Cre/R26R double transgenicマウス / 神経管形成不全 / 中脳ドーパミンニューロン / isthmic organizer / 神経堤細胞 / 交感神経上頚神経節 / 頚動脈小体 / 第3鰓弓動脈 / Mash1 / 総頚動脈 / 形成不全 / Wnt1Cre/R26Rマウス / Hes-/-マウス / 細胞分化 / tyrosine hydroxylase / Pitx3 / セロトニン / Hes- / -マウス / 頭蓋冠 / 間脳 / 下垂体隆起部 / 甲状腺C細胞 / 鰓後体 |
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| Research Abstract |
Hes genes are essential effctors of Notch signaling, which regulates the maintenance of progenitor cells and the timing of their differentiation in various tissues and organs. Hes1 represses the expression of proneural bHLH factors such as Mash1 and Ngn2, acting as a negative regulator of neuronal differentiation. The defective morphogenesis of the neural tube and exencephaly are caused in Hes1 null mutant mice. In the present study, we have indicated that Hes1 plays crucial roles for the development of many tissues in addition to neuronal epithelium
1) The hypophyseal pars tuberalis surrounds the median eminence and infundibular stalk of the hypothalamus as thin layers of cells. The pars tuberalis primordium was formed in the basal-ventral part of Rathke's pouch in the null mutants at E11.5 as well as in wild-type embryos. In contrast to the wild-type, the mutant primordium could not extend rostrally with age and disappeared at E14.5, resulting in lack of the pars tuberalis.
2) Despite
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the severe defects of neurogenesis, the mesencephalic dopaminergic(mesDA) neurons were specified in the Hes1 null mutants at the midline of the ventral mesencephalon in close proximity to two signal centers. floor plate and med/hindbrain boundary(i. e., the isthmic organizer). From E13.5 onward, the cell number and fiber density of the mesDA neurons decreased in the null mutants. Their distribution pattern was also different from that of the wild type. In particular, mesDA neurons grew dorsally and invaded the rostral hindbrain. 5-HT neurons were also ectopically located in the mutant midbrain. Thus, the loss of Hes1 resulted in disturbances in the inductive and repulsive activities of the isthmic organizer.
3) Hes1 represses the expression of proneural factor Mash1 which is essential for the differentiation of the sympathetic ganglia and carotid body glomus cells. The developments of the superior cervical ganglion(SCG) of sympathetic trunk and the glomus cells were severely affected by the loss of Hes1.At E17.5, the volume of the SCG in the Hes1 null mutants was reduced to 26.4% and the cell number was reduced to 24.5% of the values in wild-type embryos. In 4 out of 30 cases(13.4%), the common carotid artery derived from the third arch artery was absent in the null mutants, and the carotid body was not formed. When the artery was retained, the organ grew in the wall of the third arch artery. However, the volume of the carotid body in the null mutants was only 52.5% of the value in wild types at E17.5.
4) Using the Hes1 mutant mice crossed with Wnt1-Cre/R26R mice in which the neural crest lineage was labeled indelibly, we examined the role of Hes1 for the differentiation of neural crest cells in the pharyngeal region. During the early embryonic development, the mesenchymal neural crest cells colonize the pharyngeal arches and contribute to the migration and growth of the pharyngeal endoderm-derived organs including ultimobranchial body, parathyroid, thymus, and thyroid glands. In Hes1-/-・Wnt1-Cre/R26R mice, the pharyngeal arches and pouches were normally formed and the neural crest cells were distributed in each arch. However, the cell population was markedly decreased between E12.5.E13.5, when the pharyngeal organs move into their destined places. In particular, there were few neural crest cells around the primordia of thymus and parathyroid remaining close to the pharyngeal cavity. Less
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