Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/30251
Title: THE ROLES OF GLI3 IN MURINE EMBRYONIC MAMMARY GLAND DEVELOPMENT
Authors: LEE MAY YIN
Keywords: mammary gland, mouse embryo, Gli3, development
Issue Date: 5-Aug-2011
Source: LEE MAY YIN (2011-08-05). THE ROLES OF GLI3 IN MURINE EMBRYONIC MAMMARY GLAND DEVELOPMENT. ScholarBank@NUS Repository.
Abstract: The five pairs of mouse mammary glands are ectoderm-derived appendages that are formed in the embryo. The cellular and molecular mechanisms that regulate embryonic mammary gland development are largely unknown. To understand these mechanisms, I study the involvement and roles of GLI-Kruppel family member 3 (<i>Gli3</i>) in embryonic mammary gland development using the <i>Gli3<sup>Xt-J/Xt-J</sup></i> (null) mouse model. Previous studies have shown that <i>Gli3<sup>Xt-J/Xt-J</sup></i> embryos fail to induce mammary rudiment (MR) pairs 3 and 5. Here, I show that, in addition, <i>Gli3<sup>Xt-J/Xt-J</sup></i> MR2 and MR4 are severely hypoplastic and protrude outwardly. In contrast, MR1 is mildly hypoplastic but develops fairly normally. In the first part of this study, I sought to determine the cellular mechanisms that normally regulate embryonic mammary gland development and the involvement of <i>Gli3</i> in regulating these mechanisms. I show that cell migration and cell hypertrophy are the primary mechanisms that regulate induction and growth of the MRs during the first two days of mammogenesis. These cellular processes are compromised with the loss of <i>Gli3</i> , resulting in the lack of induction or hypoplasia of <i>Gli3<sup>Xt-J/Xt-J</sup></i> MRs. In the second part of the study, I sought to determine the molecular mechanisms regulated by <i>Gli3</i> in embryonic mammary gland development. Building on previous observations that <i>Wnt10b</i> is downregulated in the mammary line of <i>Gli3<sup>Xt-J/Xt-J</sup></i> embryos, I show that WNT/ß catenin signalling is downregulated during the first day of mammogenesis in <i>Gli3<sup>Xt-J/Xt-J</sup></i> embryos. Reconstitution of WNT/ß-catenin signalling using an ectoderm specific stabilized ß-catenin transgene rescues the induction of MR3, but not MR5, and attenuates the hypoplasia of MR1, MR2, and MR4 in <i>Gli3<sup>Xt-J/Xt-J</sup></i> embryos. However, proper morphogenesis was not restored in <i>Gli3<sup>Xt-J/Xt-J</sup></i> MR2 and MR3. In addition, stabilized ß-catenin did not rescue the MR phenotype of null mutants for the genes encoding fibroblast growth factor 10 (FGF10), or its main receptor FGFR2B which have lower basal levels of WNT/ß-catenin signalling compared to <i>Gli3<sup>Xt-J/Xt-J</sup></i> embryos during the first day of mammogenesis. We propose that sufficiently high levels of WNT/ß-catenin signalling are crucial in mediating MR induction and growth, but not morphogenesis. In the third part of the study, I perform a meta-analysis of reported mouse genetic models that have an embryonic MR phenotype and observed that different genes are required for the induction and morphogenesis of each MR pair. This analysis revealed that the mammogenic potential along the mammary line is different ¿ MR4 is the most resistant to compromised induction caused by single and double gene deletions, while the induction of MR3 is frequently compromised by the loss of gene function. The differential mammogenic potential could, in part, explain the diversity of mammary gland numbers and positions among the mammalian species. My MR-specific analyses in this thesis uncovered position-specific roles for <i>Gli3</i>, leading to the unexpected notion that different mechanisms are involved in the early development of these functionally-identical organs. The utilization of different molecular mechanisms represents an ingenious way of safeguarding the mammary glands in the event of an inhibitory mutation, and highlights the importance of using mammary gland-specific comparisons during research.
URI: http://scholarbank.nus.edu.sg/handle/10635/30251
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