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Dact Family Molecules in Wnt Signaling in Mouse Development Daniel Fisher Washington University in St Washington University in St. Louis Washington University Open Scholarship All Theses and Dissertations (ETDs) January 2010 Dact Family Molecules In Wnt Signaling In Mouse Development Daniel Fisher Washington University in St. Louis Follow this and additional works at: https://openscholarship.wustl.edu/etd Recommended Citation Fisher, Daniel, "Dact Family Molecules In Wnt Signaling In Mouse Development" (2010). All Theses and Dissertations (ETDs). 111. https://openscholarship.wustl.edu/etd/111 This Dissertation is brought to you for free and open access by Washington University Open Scholarship. It has been accepted for inclusion in All Theses and Dissertations (ETDs) by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. WASHINGTON UNIVERSITY IN SAINT LOUIS Division of Biology and Biomedical Sciences Program in Neurosciences Dissertation Examination Committee: Benjamin Cheyette, Chair Eugene Johnson, Co-Chair David Ornitz, Co-chair Raphael Kopan Fanxin Long Jeanne Nerbonne Joshua Rubin DACT FAMILY MOLECULES IN WNT SIGNALING IN MOUSE DEVELOPMENT By Daniel Arthur Corpuz Fisher A dissertation presented to the Graduate School of Arts and Sciences Of Washington University in Partial fulfillment of the degree Of Doctor of Philosophy December 2010 Saint Louis, Missouri Copyright by Daniel Arthur Corpuz Fisher 2010 Washington University Saint Louis, Missouri ii ABSTRACT OF THE DISSERTATION Dact family molecules in Wnt signaling in mouse development by Daniel Arthur Corpuz Fisher Doctor of Philosophy in Biology and Biomedical Sciences (Neurosciences) Washington University in Saint Louis, 2010 Benjamin Cheyette, MD, PhD, Assistant Professor of Psychiatry, UCSF, Chair Eugene Johnson, PhD, Professor Emeritus, Mentor of Record The Wnt (Wingless-Integration) molecular signaling pathways are known to be integral in the embryonic patterning of multicellular animals, and are misregulated in multiple types of cancer. Wnt signaling includes multiple biochemical signaling pathways downstream of the Wnt family of secreted proteins and their receptors. Many, and possibly all, of these pathways converge on the intracellular protein Dishevelled, whose interactions appear essential in determining the cell-autonomous effects of the Wnt signal. Dact (Dapper, Antagonist of Beta Catenin Targeting) proteins were identified based on their binding to Dishevelled. There are three Dact encoding genes in mammals, and these show unique expression patterns in the development of the mouse. A mouse mutant lacking the Dact1 gene has been constructed. Despite expression of this gene in patterns suggesting roles in somitogenesis and neuronogenesis, Dact1 mutant mice are caudally truncated due to defective mesoderm formation in late gastrulation. Dact1 mutant mice show reduced Wnt/!-catenin signaling. The Dact1 mutation and the mouse planar cell polarity mutant Loop-tail rescue one another’s phenotypes, showing iii antagonism between Wnt/!-catenin and planar cell polarity signaling pathways at the level of Dact1. Special thanks to, My mentor, Dr. Benjamin Cheyette, My thesis committee at Washington University, All members of the Cheyette laboratory, particularly my friends and collaborators Rowena Suriben and Saul Kivimäe, and Uta Grieshammer from Gail Martin’s laboratory at the University of California, San Francisco, The members of the committee of the Medical Scientist Training Program at Washington University, who supported my work, Brian Sullivan, whose assistance was priceless in coordinating the arrangements for the phase of my thesis work that was done at long distance from Saint Louis at the University of California, San Francisco, Dr. Jeanne Nerbonne, whose support and guidance helped me through the greatest challenges in my graduate education and in my life during this time, My earliest friends in laboratory science, Drs. Melanie Mark, Yuechueng Liu, and Enrique Villacrés, whose enthusiasm lit the way along the earliest steps of my path in neurologic and developmental molecular biology, My parents and family, especially my sister, Rachel Danielle, who loved for me to read to her my neuroscience textbooks when she was four years old, sitting on my shoulders in our favorite armchair, iv And especially my wife, Catherine, our son, Gabriel Keith, and our daughter, Gabriela Louise, whose love is a wonder beyond anything I can describe in words. Note on Sources of Funding: Work presented in my thesis was funded by NIH (NIGMS) RO1 grant to Dr. Benjamin Cheyette, by funds directed to him by the Department of Psychiatry and Stem Cell Center, University of California, San Francisco, and by the Medical Scientist Training Program grant to Washington University in Saint Louis. Previous work during my graduate studies was funded by the Medical Scientist Training Program, Washington University in Saint Louis, by Exelixis Pharmaceuticals, and by NIH (NINDS) grants to Dr. William D. Snider, formerly of Washington University in Saint Louis, and presently Director of the Neuroscience Institute at University of North Carolina, Chapel Hill. v Table of Contents: Chapter Page Title Page i Abstract iii Acknowlegements iv Sources of Funding v List of Figures and Illustrations vii Chapter 1, Introduction to the Thesis 1 Chapter 2, Characterization of the Dact Gene Family in Mouse Development 77 Chapter 3, Dact1 Expression in Somitogenesis 122 Chapter 4, Characterization of Dact1 Null Mice: Phenotypes, Embryology, and Signaling 149 Chapter 5, Discussion and Conclusions 201 Bibliographical References are listed following each chapter. vi List of Figures and Illustrations: Chapter 1 Page Intro. Figure 1: Cartoon depiction of Wnt signaling pathways 48 Intro. Figure 2: Comparison of Dact1 null embryonic morphology with mutants in Wnt3a and its downstream effectors 50 Intro. Figure 3: Comparison of skeletal phenotypes of Dact1 null neonates with Wnt3a mutants 52 Chapter 2 Figure 1: Dact gene family molecular data 99 Figure 2: Developmental expression of mouse Dact genes, E9.0-E10.5 101 Figure 3. Expression of Dact genes at E14.5 and in adult brain 104 Figure S1: Predicted human DACT3 sequence (H.s. Dact3) compared to translation of cloned mouse Dact3 cDNA (M.m. Dact3) 106 Figure S2: Ethidium bromide stained gels corresponding to all Northern blots shown in Fig. 1D, E 107 Fig. S3: In situ hybridization controls using reverse complementary (sense) probes 108 vii Chapter 3 Page Figure 1: Dact1 expression patterns in the PSM at E9.5 138 Figure 2: Dact1 cycles in phase with Axin2 but out of phase with Lfng 140 Figure S1: TCF/LEF binding site consensus map of the mouse Dact1 promoter region plus intron 1 142 Chapter 4 Figure 1: Caudal segmental defects in Dact1 mutant newborns 174 Figure 2: Urogenital and distal digestive tract phenotypes in Dact1 mutants 175 Figure 3: Embryonic phenotypes 177 Figure 4: Decreases in Wnt/ß-catenin pathway 178 Figure 5: Dact1 and Vangl2 are mutually antagonistic 180 Figure 6: Dact1 and Vangl2 are coexpressed in the ectoderm of the primitive streak region 182 Figure 7: Model of Dact1 function in ectoderm of the primitive streak region 184 Supplementary Figure 1: Gene targeting of the Dact1 locus in mice 186 Supplementary Table 1: Evidence for nulls 187 viii Supplementary Table 2: Mutants are born at near Mendelian ratios 187 Supplementary Table 3: Mutant phenotype spectrum 188 Supplementary Table 4: Mutant urogenital/digestive tract phenotypes 189 Chapter 4 illustrations and tables (continued) Page Supplementary Table 5: Mutant kidney malformations 189 Supplementary Figure 2: Tissue parameters in the primitive streak region 190 Supplementary Figure 3: Caudal phenotypes of E9.0 embryos from Dact1/Wnt3a intercross 191 Supplementary Figure 4: Dvl2 and p120catenin levels in the posterior mutant embryo 192 Supplementary Figure 5: Phenotypes from Wnt3a vt/vt X Vangl2 Lp/+ Wnt3a vt/+ cross 193 Additional Data, Fig. 1: Unusual hindlimb defects observed in neonatal Dact1 -/- mice 194 Additional Data, Fig. 2: Grossly normal structure of Dact1 expressing brain regions at E14 in Dact1 -/- embryos 195 Additional Data, Table 1: Lunatic fringe cycle phases observed in Dact1 -/- embryos and their littermates at E9 196 Additional Data, Fig. 3: Lunatic fringe cycle phases observed in Dact1 -/- ix E9 embryos 197 Additional Data, Fig. 4: Coexpression of Dact1 and Vangl2 in caudal embryos at E8-E8.5 199 x Chapter 1: Introduction to the Thesis. 1. Wnt, Dishevelled, and Dact molecules. 2. Structure and interactions of Dact proteins. 3. The Dact gene family. 4. Interactions of Dact beyond Dishevelled. 5. Wnt pathways: canonical and non-canonical. 6. Caudalogy: the study of caudal embryonic development as a model system. 7. Somitogenesis: Wnt3a powers the somite segmentation clock. 8. Dacts and Dact interactors in nervous system development. 9. In summary… 1 Introduction: Wnt, Dishevelled, and Dact molecules. The topic of histogenesis, or the formation of a tissue from precursor cells, has two primary components. One is cell fate, the determination of what the precursor cells are to become. The other is morphogenesis, in other words how, mechanistically, the cells form the structures which they are fated to compose. These processes involve continuing decision-points at the level of individual cells, which are typically mediated by the cell sensing an extracellular molecular signal, or morphogen, whose sensation is transduced by an array of intracellular signaling molecules to the machinery that can control
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