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Title:The role of beta-catenin in the development of fetal ovary and female germ cells
Author(s):Liu, Chia-Feng
Director of Research:Yao, Humphrey H-C.
Doctoral Committee Chair(s):Yao, Humphrey H-C.
Doctoral Committee Member(s):Bagchi, Indrani C.; Bahr, Janice M.; Bunick, David; Jorgensen, Joan S.
Department / Program:Veterinary Biosciences
Discipline:VMS - Veterinary Biosciences
Degree Granting Institution:University of Illinois at Urbana-Champaign
Activin B
Activin β b
Female germ cell
Canonical WNT pathway
Sex reversal
Sex determination
Abstract:Ovarian development in mammals is considered as a default process, arising only in the absence of Sry, a testis-determining gene. However, current evidence has suggested the presence of an active pathway in fetal ovary. In particular, gene screening experiments have shown that many genes are expressed specifically in ovary. Wingless related protein (WNT) proteins are one class among them. WNT proteins are known to be essential for embryo development in many species. Multiple WNT ligands, including the ones that signal via the canonical β-catenin pathway, are expressed in fetal gonads, suggesting their intimate association with β-catenin and potential role in regulating ovary development. Thus, the central hypothesis of my studies is that the canonical β-catenin signaling pathway is essential for the development of fetal ovary. Specifically, I conducted the studies to 1) determine the functional roles of β-catenin in the ovarian development, 2) identify the causes of female germ cell loss in the absence of WNT4/β-catenin signaling pathway, and 3) investigate the molecular connection between Wnt4 and β-catenin. In the first study of determining the functional roles of β-catenin, I generated a transgenic mouse with β-catenin being ablated specifically in the steroidogenic factor 1 (SF1)-positive population of somatic cells of the fetal gonads. In the absence of β-catenin, fetal testis developed normally whereas unique phenotypes appeared during the development of ovary. These phenotypes included formation of testis-specific coelomic vessel, appearance of androgen-producing adrenal-like cells, and the loss of female germ cells. The observed phenotypes were similar to those found in the R-spondin1 (Rspo1) and Wnt4 knockout (KO) ovaries, indicating that these three factors were in the same pathway to regulate ovary development. In addition, the expression of Wnt4 was abolished whereas the expression of Rspo1 was unaltered, which placed β-catenin as a mediator between RSPO1 and WNT4. My second study determined what caused female germ cell loss in the absence of WNT4/β-catenin signaling pathway. The observations of the ectopic androgen production and the upregulated inhibin β b (Inhbb) expression were also found, along with germ cell loss, in the Wnt4 KO and β-catenin conditional KO (cKO) ovaries suggesting these two to be the potential causes of female germ cell loss. Female germ cells were still lost in the β-catenin cKO embryos after treating with flutamide, an anti-androgen drug. This result ruled out the ectopic androgen production from being responsible for germ cell loss. On the other hand, the number of germ cells was restored in the Wnt4 and Inhbb double KO indicating that Inhbb was the cause of female germ cell loss in the absence of WNT4/β-catenin pathway. In my third study, I investigated the molecular connection between Wnt4 and β-catenin. I demonstrated that activation of the stabilized form of β-catenin prevented the appearance of male-specific characteristics during the ovarian development and also supported the survival of female germ cells. The results indicated that β-catenin served in the downstream of WNT4 in the somatic cells of fetal ovary to regulate fetal ovary and female germ cell developments. In summary, WNT4/β-catenin pathway is essential for the maintenance of ovarian identities and the survival of female germ cells. WNT4 acts on the SF1-positive somatic cells to activate β-catenin. The activated β-catenin prevents the male-specific phenotypes from appearing in the mouse ovary. The survival of female germ cells hinges upon a delicate balance between the somatic cell-derived factors: WNT4 maintains the survival of female germ cells by suppressing Inhbb expression in the somatic cells via β-catenin.
Issue Date:2010-05-14
Rights Information:© 2010 Chia-Feng Liu
Date Available in IDEALS:2010-05-14
Date Deposited:May 2010

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