title: The Influence of LepR Tyrosine Site Mutations on Mouse Ovary Development and Related Gene Expression Changes.
abstract: Leptin exerts many biological functions, such as in metabolism and reproduction, through binding to and activating the leptin receptor, LepRb, which is expressed in many regions of the brain. To better understand the roles of LepR downstream signaling pathways, Y123F mice, which expressed mutant leptin receptors with phenylalanine (F) substituted for three tyrosines (Y) (Tyr985, Tyr1077 and Tyr1138), were generated. The body weight and abdominal fat deposits of Y123F homozygous mice (HOM) were higher than those of wild-type mice (WT). HOM ovaries were atrophic and the follicles developed abnormally; however, the HOM ovaries did not exhibit polycystic phenotypes. Moreover, Y123F HOM adults had no estrous cycle and the blood estrogen concentration remained stable at a low level below detection limit of 5 pg/ml. LepR expression in HOM ovaries was higher than in WT ovaries. Using cDNA Microarrays, the mRNA expressions of 41 genes were increased, and 100 were decreased in HOM vs. WT ovaries, and many signaling pathways were evaluated to be involved significantly. The expressions of 19 genes were validated by real-time quantitative PCR, most of which were consistent with the microarray results. Thus, Y123F HOM mice were suggested as a new animal model of PCOS for research that mainly emphasizes metabolic disorders and anovulation, but not the polycystic phenotype. Meanwhile, using the model, we found that JAK-STAT and hormone biosynthesis pathways were involved in the follicular development and ovulation disorders caused by LepR deficiency in ovaries, although we could not exclude indirect actions from the brain.
authors.affiliation: Shanghai Medical College, Institute of Reproduction and Development, Fudan University, Shanghai, P. R. China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Tu
authors.affiliation: Shanghai Medical College, Institute of Reproduction and Development, Fudan University, Shanghai, P. R. China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Kuang
authors.affiliation: Department of Food Science, Shanghai Business School, Shanghai, P. R. China.
authors.forename: Xia
authors.initials: X
authors.lastname: Gong
authors.affiliation: Key Laboratory of Contraceptive Drugs and Devices of National Population and Family Planning Commission of China, Shanghai Institute of Planned Parenthood Research, Shanghai, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Key Laboratory of Contraceptive Drugs and Devices of National Population and Family Planning Commission of China, Shanghai Institute of Planned Parenthood Research, Shanghai, P. R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yu
authors.affiliation: Key Laboratory of Contraceptive Drugs and Devices of National Population and Family Planning Commission of China, Shanghai Institute of Planned Parenthood Research, Shanghai, P. R. China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Shi
authors.affiliation: Key Laboratory of Contraceptive Drugs and Devices of National Population and Family Planning Commission of China, Shanghai Institute of Planned Parenthood Research, Shanghai, P. R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Contraceptive Drugs and Devices of National Population and Family Planning Commission of China, Shanghai Institute of Planned Parenthood Research, Shanghai, P. R. China.
authors.forename: Zhaogui
authors.initials: Z
authors.lastname: Sun
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D030762:Estrous Cycle; D005260:Female; D005786:Gene Expression Regulation; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D006080:Ovarian Follicle / Q000254:growth & development*; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D054411:Receptors, Leptin; C515447:leptin receptor, mouse