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Functional Analysis of the Homeobox Gene Tur-2 During Mouse Embryogenesis

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Functional Analysis of The Homeobox Gene Tur-2 During Mouse Embryogenesis Shao Jun Tang A thesis submitted in conformity with the requirements for the Degree of Doctor of Philosophy Graduate Department of Molecular and Medical Genetics University of Toronto March, 1998 Copyright by Shao Jun Tang (1998) National Library Bibriothèque nationale du Canada Acquisitions and Acquisitions et Bibiiographic Services seMces bibliographiques 395 Wellington Street 395, rue Weifington OtbawaON K1AW OttawaON KYAON4 Canada Canada The author has granted a non- L'auteur a accordé une licence non exclusive licence alIowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distri%uteor sell reproduire, prêter' distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/nlm, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fkom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. Functional Analysis of The Homeobox Gene TLr-2 During Mouse Embryogenesis Doctor of Philosophy (1998) Shao Jun Tang Graduate Department of Moiecular and Medicd Genetics University of Toronto Abstract This thesis describes the clonhg of the TLx-2 homeobox gene, the determination of its developmental expression, the characterization of its fiuiction in mouse mesodem and penpheral nervous system (PNS) developrnent, the regulation of nx-2 expression in the early mouse embryo by BMP signalling, and the modulation of the function of nX-2 protein by the 14-3-3 signalling protein during neural development. TL.-2 is a murine horneobox gene related to the hurnan T-ce11 leukemia oncogene HOXII. During early mouse development, 77x-2 is expressed in the ectodem and the primitive streak. In vivo and Ni vitro experiments dernomte that BMP2/4 signalling activates the expression of i7.x-2, suggesting that during mouse embryogenesis Th2 is a downstream target gene in a BMP signalling pathway. A targeted mutation of TLr-2 Ieads to early embryonic lethality, and the homozygous embryos display severe defects in the primitive streak and in mesoderm formation. The phenotype of TLx-2 mutant embryos demonstrate an essential role of TLc-2 in mouse mesoderm formation, a developmental process regulated by BMP 24signalling. These hdings suggest a BMPmx-2 signallhg pathway required for mammaiian mesoderm development. TLr-2 is specifïcally exgressed in the developing PNS after E9.0, including the sensory and autonomie ganglia derived fkom the neural crest. A role for 71.-2 in PNS development is suggested by the coincidence of the evolution of the T2x-2 expression pattern and the ontogenesis of the PNS. Overexpression of îE-2 in PC 12 cells suppresses neurite outgrowth induced by NGF, indicating that 7k-2 is a negative regulator of neural differentiation. Furthermore, TLX-2 is a transcription repressor as demonstrated by CO-transfectionassays. These results suggest that 77x-2 suppresses neuronal differentiation during the early phase of gangliogenesis. probably by its repression of neuronal gene expression. TLX-2 is associated with the 14-3-3 q protein both in vitro and in vivo. The physiological significance of the physical interaction of TLX-2 and 14-3-3 q is demonstrated at several leveis: TLr-2 and 14-3-3 r] are CO-expressedin the developing PNS and in PC 12 cells, 14-3-3 q enhances the nuclear localization of TLX-2, and 14-3-3 q and TLX-2cooperatively suppress neurite outgrowth of PC 12 cells. These results indicate that the function of the IXX-2 homeodomain is probably regulated by ce11 signalling mediated by 14-3-3 proteins. This work contributes to an understanding of the function the Tlx-2 homeobox gene and of the regdation of the TLx-2 function during mouse embryogenesis. and provides novel insights into the molecular control of mouse mesoderm and PNS develo pment. Acknowledgments I thank everyone who have encouraged and helped me during the course toward to my Ph. D. My first debt is to the codttee members, Drs. Manuel Buchwald. Joe Culotti and Rod Mches, for their very helpful advice. I thank Drs. Manuel Buchwald and Rod Mchess for their patient guidance. 1 am most grateful to Dr. Manuel Buchwald for his invaluable support, which has allowed me to finish this work. 1 owe a tremendous debt to my former supervisor, Dr. Martin L. Breitman. who sadly passed away when I initiated this work for the encouragement he was always willing to offer, even when he was suffering from the terminal illness of cancer. 1 thank ail members in the Buchwald and the McIness laboratones for their kindness, especially Zhan Lu, Jeff Lighâoot, Rob Cumming, Jasmine Wang, Linda Parker, Geoff Clarke, and Lynda Ploder for their help. To the rnembers of the Department of Genetics and the Program of Developmental Biology at the Hospital For Sick Children, thanks for making this enviroment an exciting and fi-iendly place for science. 1 would especially like to thank Peny Howard, Michael Crackower. Ting-Chung Suen, Pamela Hoodless, Jeff Wrana, and Ching-Chung Hui for their stimulating discussions and help. Finally, 1 would like to thank al1 my family members, especially my wife and my parents for their love and enonnous support. Table of Contents Abstract of Thesis .............................................................................. 1 Acknowledgments ............................................................................. .III Table of Contents ............................................................................... IV List of Tables ................................................................................... -1X List of Figures ................................................................................... IX Chapter 1. Introduction ........................................................................ 1 1.1. Gastdation of the mouse embryo ........................................................ 2 1.1.1. An overview ................................................................................ 2 1.1.2. Proliferation and movement of the epiblast cells .......................................4 1.1.3. Formation of the mouse mesodenn: embryonic and cellular aspects ................ 9 1.1.4. Molecular aspects ofmouse mesoderm development ............................... 11 1.1.4.1. Inductive signais for mesoderm formation.......................................... 11 1.1.4.2. The function of transcription factors during mouse mesoderm development.............................................................. -16 1.2. Development of the mouse peripheral nervous system (PNS) ........................ 18 1.2.1. Embryological and molecular aspects of the neural crest ongin .................... 18 1.2.2. Embryological and molecular aspects of mouse PNS development ............... -23 1.3. Regdation of the function of homeobox genes during developrnent ................ 32 1 .3.1 .The role of homeobox genes in development.......................................... 32 1.3.2 . Regdation of the hinction of homeobox genes ...................................... -32 1.3.2.1 .Regulation of developmental expression of homeo box genes ....................32 1.3.2.2. Regulation of the biologicai fhction of homeobox genes by mRNA localization and translation ............................................................ -37 1.3.2.3. Regdation of the biological activity of homeodomain proteins ................. -39 1.4. HOXl 1 and TLc homeobox-containing genes ............................................ 42 1.5 . Objectives of this midy .................................................................... -44 1 .6 . References.................................................................................... 45 Chapter 2. Regulation of mammalian mesoderm development by a BMPlTix-2 signailhg pathway ................................................ 65 2.1. Absmct ...................................................................................... -66 2.2. Introduction .................................................................................. 67 2.3. Materials and methods ..................................................................... -69 2.4. Results....................................................................................... 71 2.4.1. Identification and early expression of 2%-2 ............................................ 71 2.4.2. Activation of Tl'-2 expression by BMP signalhg ................................... 74 2.4.3. The TlX-2 targeted mutation causes early embryonic lethality .......................80 2.4.4. Phenotypic effects of the TLr-2 mutation in the primitive streak, mesodem and ectoderm of the homozygous embryo .............................. 87 2.5. Discussion ................................................................................... -93 2.5.1. TLx-2 is a direct target gene for BMP signalling ....................................... 93 2.5.2. 77x-2 fiuictions as a mediator of BMP signalhg in primitive streak and mesoderm development ............................................................ 95 2.6. References ................................................................................... -98
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