Molecular Mechanisms of Gonadal Sex Differentiation

性腺性别分化的分子机制

• 批准号: 14370332
• 负责人: MOROHASHI Ken-ichirou
• 金额: $ 8.9万
• 依托单位: Okazaki National Research Institutes
• 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 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370332/
• 关键词: Ad4BP; SF-1; Nuclear Receptor; ARX; Gonad; Gene Disrupted Mouse; SUMO; Sex; 転写因子; 細胞極性; 性分化

Gonad is the tissue showing the most prominent sexual difference. Moreover, the gonad induces sex differentiation of other tissues through production of sex steroid hormones. The following studies were performed to elucidate the molecular mechanisms underlying gonad sex differentiation.(1)Vinexine was isolated as a protein interacting with Ad4BP/SF-1. Since the expression was detected in the developing fetal gonads, the gene KO mouse was generated and the phenotype was examined. Interestingly, the KO mouse showed XY sex reversal and phosphorylation of ERK was reduced significantly in the male fetal gonad.(2)Functions of a homeo box protein, Arx, were examined with the gene KO mouse, and found that Arx is involved in Leydig cell differentiation. Moreover, the gene mutation was found to cause a human disease, X-linked lissencephaly with abnormal genitalia.(3)With respect to posttranslational modification of Ad4BP/SF-1, we revealed that Ad4BP/SF-1 is SUMOylated and phosphorylated. SUMOylation suppressed transcriptional activity. Interestingly, Sox9 was also SUMOylated and the SUMOylation of these two transcription factors suppressed their synergistic transcription of the MIS gene. The effects of phosphorylation is still under investigation.

性腺是表现出最显着的性别差异的组织。此外，性腺通过产生性类固醇激素诱导其他组织的性别分化。进行了以下研究来阐明性腺性别分化的分子机制。(1)Vinexine作为与Ad4BP/SF-1相互作用的蛋白质被分离出来。由于在发育中的胎儿性腺中检测到表达，因此产生了基因KO小鼠并检查了表型。有趣的是，KO小鼠表现出XY性别逆转，雄性胎儿性腺中ERK磷酸化显着降低。(2)用基因KO小鼠检测同源盒蛋白Arx的功能，发现Arx参与Leydig细胞分化。此外，还发现该基因突变会导致人类疾病——X连锁无脑畸形伴生殖器异常。(3)关于Ad4BP/SF-1的翻译后修饰，我们发现Ad4BP/SF-1被SUMO化和磷酸化。 SUMO化抑制转录活性。有趣的是，Sox9 也被 SUMO 化，并且这两个转录因子的 SUMO 化抑制了它们对 MIS 基因的协同转录。磷酸化的影响仍在研究中。

项目成果

Taiga Suzuki, et al.: "LXXLL motifs in Dax-1 have target specificity for the orphan receptors Ad4BP/SF-1 and LRH-1."Mol.Cell.Biol.. 23. 238-249 (2003)

Taiga Suzuki 等人：“Dax-1 中的 LXXLL 基序对孤儿受体 Ad4BP/SF-1 和 LRH-1 具有靶标特异性。”Mol.Cell.Biol.. 23. 238-249 (2003)

Mitsuhiro Kato, et al.: "Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation"Human Mutation. 23. 147-159 (2003)

Mitsuhiro Kato 等人：“ARX 突变与显着的多效性和一致的基因型-表型相关性相关”人类突变。

諸橋 憲一郎 他: "核内レセプターと生殖腺の性分化"遺伝子医学. 6(4). 35-38 (2002)

Kenichiro Morohashi 等人：“性腺的核受体和性别分化”，遗传医学 6(4)。

諸橋 憲一郎: "生殖腺の分化とオーファンレセプター"Molecular Medicine. 39(3). 270-276 (2002)

Kenichiro Morohashi：“性腺分化和孤儿受体”分子医学 39(3)。

R.Asoy, et al.: "Activation of cAMP-dependent protein kinase increases the protein level of steroidogenic factor-1"Endocrinology. 143(1). 295-303 (2002)

R.Asoy 等人：“cAMP 依赖性蛋白激酶的激活会增加类固醇生成因子 1 的蛋白水平”内分泌学。