Functional Analysis of Oxytocin Receptor with the Receptor Knockout Mice

受体敲除小鼠催产素受体的功能分析

• 批准号: 14360046
• 负责人: NISHIMORI Katsuhiko
• 金额: $ 9.34万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14360046/
• 关键词: Oxytocin; Oxytocin Receptor; Parturition; Fp Receptor; Agrressive Behavior; Maternal Behavior; Obesity; Thermo Regulation; プロスタグランジンF2α; Ep3プロスタグランジン受容体; RU486; 受容体; レジテントイントゥルーダーテスト; 射乳; 行動異常; GPCR

The oxytocin receptor (OXTR) has been considered to be essential for reproductive physiology and sociosexual behaviors. However, OXT-deficient (Oxt-/-) mice displayed defects only in milk ejection and social recognition. To analyze the roles of the OXTR in the reproductive and central nervous systems, we generated mice lacking the Oxtr gene (Oxtr-/-). <Reproductive Function> Oxtr-/-mice exhibited normal rates of mating, pregnancy, and litter sizes, demonstrating that OXTR is not essential for either male or female reproductive function. Although Oxtr-/-females showed no obvious defect in parturition, all offspring of Oxtr-/-females died after birth. Histological analysis of mammary glands in postpartum Oxtr-/-females indicated that ducts accumulated milk. <Sociosexual Behavior> Postpartum Oxtr-/-females displayed the impairment of maternal behavior. Virgin Oxtr-/-females displayed a similar phenotype, suggesting that OXTR is required for nurturing responses to pups outside the physiolo … More gical context of pregnancy and parturition. We observed more wounded mice in group-housed males from cages containing Oxtr-/-mice than in cages containing only Oxtr+/+ mice, we assessed aggressive behavior using the resident-intruder test. Oxtr-/-mice showed elevated aggressive behavior. However, plasma testosterone concentrations were not significantly different between Oxtr+/+ and Oxtr-/-mice. In contrast, in cages containing OXT-knockout (Oxt-/-) males, the rate of wounded mice was similar to that in Oxt+/+ mice. Furthermore, aggressive behavior of Oxt-/-mice in the resident-intruder test was indistinguishable from Oxt+/+ mice. This discrepancy in aggression phenotypes between Oxtr-/-and Oxt-/-mice potentially implicates OXT-independent activation of OXTR in Oxt-/-mice. <Other function of OTR> Male otr-/-mice developed obesity by 15 week old but female did not. Histlogical analysis of adipose tissue in male otr-/-mice showed lipid accumulation in gonadal white adipose tissue (WAT), and most of cells in brown adipose tissue (BAT) were filled with large lipid droplets, suggesting a typical feature in dysfunction of thermogenesis. When otr-/-mice were exposed to cold, their rectal temperature dropped rapidly. Cold-sensitive was mostly accompanied by failure to induce thermogenic mechanism in BAT. In otr-/-mice, the ratio of α2 to β3 adrenergic receptors (ARs) expressing in BAT was altered in comparison with that in wildtype animals. As α 2 and β3 ARs were known to have opposite effects in thermogenesis, the inbalance of these ARs might attenuate energy expenditure accompanied with less thermogenesis, possibly leading to obesity. Less

催产素受体（OXTR）被认为是生殖生理和社会性行为所必需的。然而，OXT缺陷（OXT-/-）小鼠仅在乳汁排出和社会识别方面表现出缺陷。为了分析OXTR在生殖和中枢神经系统中的作用，我们产生了缺乏OXTR基因的小鼠（OXTR-/-）。<Reproductive Function>OXTR-/-小鼠表现出正常的交配率、妊娠率和窝仔数，表明OXTR对雄性或雌性生殖功能都不是必需的。虽然Oxtr-/-雌性在分娩中没有表现出明显的缺陷，但所有的后代都在出生后死亡。产后Oxtr-/-女性乳腺的组织学分析表明，导管积累牛奶。<Sociosexual Behavior>产后Oxtr-/-女性表现出母性行为的损害。未交配过的OXTR-/-雌性动物表现出相似的表型，表明OXTR是在生理条件外对幼崽进行养育反应所必需的。 ...更多信息 怀孕和分娩的心理背景。我们观察到在含有Oxtr-/-小鼠的笼中的分组圈养雄性中受伤的小鼠比仅含有Oxtr+/+小鼠的笼中更多，我们使用居民-入侵者测试评估攻击行为。Oxtr-/-小鼠表现出更高的攻击行为。然而，血浆睾酮浓度在Oxtr+/+和Oxtr-/-小鼠之间没有显著差异。相比之下，在含有OXT敲除（Oxt-/-）雄性的笼中，受伤小鼠的比率与Oxt+/+小鼠相似。此外，Oxt-/-小鼠在居民-入侵者测试中的攻击行为与Oxt+/+小鼠无法区分。Oxtr-/-和Oxt-/-小鼠之间的攻击表型的这种差异可能涉及Oxt-/-小鼠中OXTR的OXT非依赖性激活。<Other function of OTR>雄性otr-/-小鼠在15周龄时出现肥胖，但雌性小鼠则没有。对雄性otr-/-小鼠脂肪组织的组织学分析显示，性腺白色脂肪组织（WAT）中脂质积聚，棕色脂肪组织（BAT）中大部分细胞充满大的脂滴，提示产热功能障碍的典型特征。当otr-/-小鼠暴露在寒冷中时，它们的直肠温度迅速下降。BAT的冷敏感性大多伴随着不能诱导产热机制。在otr-/-小鼠中，BAT中表达的α2与β3肾上腺素能受体（AR）的比例与野生型动物相比发生了变化。由于已知α 2和β3 AR在产热方面具有相反的作用，这些AR的不平衡可能会减少能量消耗，同时减少产热，可能导致肥胖。少

项目成果

遺伝子欠損マウスによるオキシトシン・オキシトシン受容体システムの機能解析

使用基因缺陷小鼠进行催产素和催产素受体系统的功能分析

• 发表时间: 2002
• 期刊: 日本農芸化学会誌(ミニレビュー) 76
• 作者: 西森克彦 他

Kimura, T. et al.: "Molecular regulation of the oxytocin receptor in peripheral organs"J. Endocrinol.. (in press). (2003)

Kimura, T. 等人：“外周器官中催产素受体的分子调节”J。

Tumor metastasis-associated human MTA1 gene and its MTA1 protein product:: Role in epithelial cancer cell invasion, proliferation and nuclear regulation

• DOI: 10.1023/a:1022534217769
• 发表时间: 2003-01-01
• 期刊: CLINICAL & EXPERIMENTAL METASTASIS
• 影响因子: 4
• 作者: Nicolson, GL;Nawa, A;Moustafa, A
• 通讯作者: Moustafa, A

Kawamata, M. et al.: "Vasopressin-induced contraction in the mouse uterus is mediated only by oxytocin receptor, but not in the human uterus"Eur. J. Pharmacology. (in press). (2003)

Kawamata, M. 等人：“加压素诱导的小鼠子宫收缩仅由催产素受体介导，但在人类子宫中则不然”Eur。

The well-known hormone oxytocin and its GPCR receptor OXTR, and the newly found orphan GPCRLGR4 ; In vivo functions of those ligand and receptors, deduced from mice deficient in those genes

众所周知的激素催产素及其GPCR受体OXTR，以及新发现的孤儿GPCRLGR4；

• 发表时间: 2004
• 期刊: Rinsho Kagaku 33
• 作者: Nishimori;K.;Kato;S.;Kawamata;M.;Takayanagi;Y.
• 通讯作者: Y.