The role of sex steroid on the generation of sex differences in the brain development with special attention to androgen.

性类固醇对大脑发育中性别差异产生的作用，特别关注雄激素。

• 批准号: 13470335
• 负责人: TANAKA Junya
• 金额: $ 7.49万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470335/
• 关键词: MICROGLIA; ESTOSTERONE; AQUAPORIN; ASTROCYTES; NEURON; APOLIPOPROTEINE; L-Ser; L-Ser; progesterone; アストロサイト; マイクログリア; テストステロン; 性ホルモン受容体; プロゲステロン; RT-PCR; 脳の性差形成; アクアポーリン; アンドロゲン; アクアポーリン4; 細胞の生存率; タンパク質キナーゼC; 神経細胞

1)Microglia and astrocytes were found to express receptors for androgen as revealed by RT-PCR study.2)Based on comprehensive experiments with RT-PCR technique, testosterone was found to increase the expression of mRNA encoding aquaporin 4 in astrocytes. Not only testosterone but progesterone and dehydrotestosterone also upregulated the expression of aquaporin 4 at both mRNA and protein level. Protein kinase C (PKC) activator phorbol ester abolished the testosterone-induced increase of aquaporin 4. This suggests that the action of androgen is dependent on the action of PKC.3) Microglia of mesodermal origin have prosperities resembling monocytes/macrophages. We have found that microglia possess a nature as a multipotential neural stem cells. By incubating microglial cells in culture medium containing 70% serum, the cells came to have a nature as undifferentiated stem cells. The stem-like microglia differentiated into neurons or oligodendrocytes after they were transferred into serum-free medium. Testosterone enhanced the transformation of microglial cells into cells with neuroectodermal phenotypes through the undifferentiated cells. Furthermore, testosterone altered the expression pattern of mRNAs encoding GFAP.4)Microglial cells were found to produce and release lipoproteins containing apolipoprotein E, cholesterol, phospholipids and triglycerides in the presence of L-Ser. Testosterone elicited inhibitory effects on the release of lipoproteins by microglial cells.

1)RT-PCR结果显示小胶质细胞和星形胶质细胞表达雄激素受体。2）通过RT-PCR技术的综合实验，发现睾酮可增加星形胶质细胞水通道蛋白4（AQP 4）mRNA的表达。不仅睾酮，而且孕酮和脱氢睾酮也在mRNA和蛋白水平上调水通道蛋白4的表达。蛋白激酶C（PKC）激活剂佛波酯取消睾酮诱导的水通道蛋白4的增加。这表明雄激素的作用依赖于PKC的作用。3）中胚层来源的小胶质细胞具有类似单核细胞/巨噬细胞的特性。我们发现小胶质细胞具有多潜能神经干细胞的性质。通过在含有70%血清的培养基中孵育小胶质细胞，细胞具有未分化干细胞的性质。干细胞样小胶质细胞在无血清培养液中分化为神经元或少突胶质细胞。替吉奥促进小胶质细胞通过未分化细胞向神经外胚层表型细胞转化。4）在L-Ser存在下，小胶质细胞可产生和释放脂蛋白，包括载脂蛋白E、胆固醇、磷脂和甘油三酯，睾酮可抑制小胶质细胞释放脂蛋白。

项目成果

Wen T-C, Tanaka J, Hata R, Desaki J, Sato K, Nakata K, Ma Y-J, Sakanaka M: "Erythropoietin protects neurons against chemical hypoxia and cerebral ischemic injury by upregulating Bcl-xL expression."Journal of Neuroscience Research. 67. 795-803 (2002)

Wen T-C、Tanaka J、Hata R、Desaki J、Sato K、Nakata K、Ma Y-J、Sakanaka M：“促红细胞生成素通过上调 Bcl-xL 表达来保护神经元免受化学缺氧和脑缺血损伤。”神经科学研究杂志。

A Yokoyama, L Yang, S Itoh, K Mori, Junya Tanaka: "Microglia, a potential source of neurons, astrocytes, and oligodendrocytes."Glia. 45. 96-104 (2004)

A Yokoyama、L Yang、S Itoh、K Mori、Junya Tanaka：“小胶质细胞，神经元、星形胶质细胞和少突胶质细胞的潜在来源。”神经胶质细胞。

Y Kuwabara, A Yokoyama, L Yang, K Toku, K Mori, I Takeda, T Shigekawa, B Zhang, N Maeda, M Sakanaka, Junya Tanaka: "Two populations of microglial cells isolated from rat primary mixed glial cultures"Journal of Neuroscience Research. 73. 22-30 (2003)

Y Kuwabara、A Yokoyama、L Yang、K Toku、K Mori、I Takeda、T Shigekawa、B 张、N Maeda、M Sakanaka、Junya Tanaka：“从大鼠原代混合神经胶质培养物中分离出的两个小胶质细胞群”神经科学杂志

F.Gu, R.Hata, K.Toku, L.Yang, Y.-J.Ma, N.Maeda, M.Sakanaka, J.Tanaka: "Testosterone upregulates aquaporin-4 expression in cultured astrocytes"Journal of Neuroscience Research. (in press).

F.Gu、R.Hata、K.Toku、L.Yang、Y.-J.Ma、N.Maeda、M.Sakanaka、J.Tanaka：“睾酮上调培养的星形胶质细胞中的水通道蛋白 4 表达”神经科学研究杂志

Zhang B, Yang L, Konishi Y, Maeda N, Sakanaka M, Tanaka J.: "Suppressive effects of phosphodiesterase type IV inhibitors on rat cultured microglial cells : Comparison with other types of cAMP-elevating agents."Neuropharmacology. 42. 262-269 (2002)

张B，杨L，小西Y，前田N，坂中M，田中J.：“磷酸二酯酶IV型抑制剂对大鼠培养的小胶质细胞的抑制作用：与其他类型的cAMP升高剂的比较。”神经药理学。