Uniform TitleThe inhibitor of DNA binding proteins in celluar proliferation and differentiation: regulation by the retinoic acid signaling pathway
NameVillano, Caren M. (author), White, Lori (chair), Cooper, Keith (internal member), Richardson, Jason (internal member), Gordon, Marion (internal member), Quadro, Loredana (outside member), Rutgers University, Graduate School - New Brunswick,
DescriptionThe Id (Inhibitor of differentiation or DNA binding) helix-loop-helix proteins mediate cellular differentiation and proliferation in a variety of cell types through regulation of gene expression. The goal of the experiments in this thesis is to determine the effect of the retinoic acid signaling pathway on Id expression using cell culture and whole animal models. Retinoids, vitamin A analogues, are powerful regulators of cell growth and differentiation and are widely used in the prevention and treatment of a variety of cancers in humans. We found that exposure of normal human keratinocytes to all-trans retinoic acid (RA) results in increased expression of Id1 and Id3, which is mediated by increased transcription involving cis- acting elements in the distal portion of the promoter. To examine the effect of the Id proteins in development, we used the zebrafish (Danio rerio) model. Morpholino knockdown of Id1 in the developing zebrafish embryo results in pericardial, yolk sac and/or brain edema, as well as an undulating notochord. Loss of Id1 in early zebrafish embryogenesis results in defects in larval development, such as decreased body size, lack of swim bladder inflation, and craniofacial defects. We conclude that Id1 is critical for early and late zebrafish development. Our findings also demonstrate that RA exposure decreases expression of Id1 specifically in the heart, and RA deficiency results in increased Id1 expression. Id1 knockdown results in increased expression of the cardiac-specific transcription factors gata5 and nkx2.5 which are also targets of the RA signaling pathway. To further examine the role of Id1 in differentiation and proliferation, we examined Id expression during caudal fin regeneration. Our data demonstrate that Id1 expression is induced in the blastema during caudal fin regeneration, and that exposure to RA during regeneration decreases Id1 expression. Taken together, the data presented in this thesis demonstrate that Id1 is a target for RA signaling in both human skin cells and in zebrafish. Further, these data suggest that Id1 may be an important intermediate in the RA signaling pathway, by altering expression of genes involved in proliferation and differentiation.
NoteIncludes bibliographical references (p. 115-131).
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.