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Permanent link (DOI): https://doi.org/10.7939/R38P5VQ3B

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Functional Characterization of Homeodomain Transcription Factors and Retinoic Acid Signaling in Hematopoiesis Open Access

Descriptions

Other title
Subject/Keyword
Hematopoiesis
Primitive Hematopoiesis
Definitive Hematopoiesis
Retinoic Acid
Homeodomain Transcription Factors
Pbx
Meis1
Hmx4
Zinc Finger Nuclease
TALEN
Sharkey
Zebrafish
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Laura Pillay
Supervisor and department
Waskiewicz, Andrew J. (Biological Sciences)
Examining committee member and department
Waskiewicz, Andrew J. (Biological Sciences)
Pilgrim, David B. (Biological Sciences)
Ali, Declan W. (Biological Sciences)
McDermid, Heather E. (Biological Sciences)
Sagerstrom, Charles G. (Biochemistry and Molecular)
Pharmacology, University of Massachusetts Medical School)
Department
Department of Biological Sciences
Specialization
Molecular Biology and Genetics
Date accepted
2015-01-05T09:58:05Z
Graduation date
2015-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Improper regulation of hematopoiesis generates a spectrum of defects that range from anemia and embryonic lethality to leukemia. Identifying the molecular pathways that regulate hematopoiesis is therefore a major goal of both basic and clinical biology. Vertebrate hematopoiesis occurs in two embryonic waves. The first wave, primitive hematopoiesis, influences the morphology of the developing embryonic circulatory system and produces circulating erythrocytes that facilitate tissue oxygenation during periods of rapid embryonic growth. The second, definitive wave of hematopoiesis produces multipotent hematopoietic stem cells (HSCs) that are able to differentiate into all mature blood cell lineages, self-renew, and maintain adult hematopoiesis for life. A major challenge in developmental hematopoiesis is to determine the molecular cues that regulate each phase of hematopoiesis. Previous analyses using vertebrate models have identified molecular pathways that govern both primitive and definitive hematopoiesis. These pathways are conserved among vertebrates, and the critical mammalian hematopoietic genes have clear orthologues in zebrafish. Using zebrafish as a model organism, we have identified essential regulators of both primitive and definitive hematopoiesis. We have defined a critical role for the homeodomain transcription factors Meis1 and Pbx in regulating primitive erythropoiesis. Inhibiting zebrafish Meis1 and Pbx protein synthesis cripples the production of circulating erythrocytes, and generates defects in erythropoietic gene expression. Our data place Meis1 and Pbx upstream of gata1 in the erythropoietic transcription factor hierarchy. We have also elucidated a novel role for retinoic acid (RA) signaling in definitive hematopoiesis, as RA-depleted embryos fail to produce HSCs. Previous studies have implicated RA as a critical regulator of murine Notch1 signaling, and suggest that endothelial cells require RA in order to adopt a hemogenic fate. However, our research suggests that RA is required for HSC formation prior to the formation of dorsal aorta hemogenic endothelium and that, unlike in mice, zebrafish RA does not regulate HSC formation through the Notch1-signaling pathway. Previous research by our lab has implicated the homeodomain transcription factor Hmx4 as a critical regulator of zebrafish forebrain and ocular development, and has shown that Hmx4 modulates RA signaling. However, prior to this work, the contribution of Hmx4 to embryonic hematopoiesis was unknown. We have identified putative RA-independent and dependent roles for Hmx4 in regulating primitive and definitive hematopoiesis, respectively.
Language
English
DOI
doi:10.7939/R38P5VQ3B
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Laura M. Pillay, A. Michael Forrester, Timothy Erickson, Jason N. Berman, and Andrew J. Waskiewicz (2010). The Hox cofactors Meis1 and Pbx act upstream of gata1 to regulate primitive hematopoiesis. Developmental Biology, 340(2):306-317. Patricia A. Gongal, Lindsey D. March, Vanessa L. Holly, Laura M. Pillay, Karyn M. Berry-Wynne, Hiroyuki Kagechika, and Andrew J. Waskiewicz (2011). Hmx4 regulates Sonic hedgehog signaling through control of retinoic acid synthesis during forebrain patterning. Developmental Biology, 355(1): 55-64. Laura M. Pillay, Lyndsay G. Selland, Valerie C. Fleisch, Patricia L. A. Leighton, Caroline S. Cheng, Jakub K. Famulski, R. Gary Ritzel, Lindsey D. March, Hao Wang, W. Ted Allison, and Andrew J. Waskiewicz (2013). Evaluating the mutagenic activity of targeted endonucleases containing a Sharkey FokI cleavage domain variant in zebrafish. Zebrafish, 10(3): 353-364.

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