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Title:Limb cell behaviors in Monodelphis domestica growth and development: the effects of Fgf pathway activators and inhibitors
Author(s):Dowling, Anna
Advisor(s):Sears, Karen E.
Department / Program:School of Integrative Biology
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Limb development
Fgf/MAPK signaling pathway
differential organ growth
hind limb
Abstract:A fundamental question in biology is, “how is growth differentially regulated during development to produce organs of particular sizes?” Research in invertebrates has shown that answers to this question can be gained by studying how serially homologous organs of a single animal (e.g., Drosophila wing and haltere) become different sizes. However, the phenotypes of most traditional model vertebrates (e.g., mouse, chick) do not readily lend themselves to this approach. As a result, the mechanisms that control the growth and size of vertebrate organs remain poorly understood. This represents a fundamental gap in our knowledge, which severely limits our understanding of the many growth-related aspects of organ development, evolution and health in vertebrates. In my thesis, I took advantage of a new model system for the study of differential organ growth, the limbs of the opossum (Monodelphis domestica) to investigate the cellular and molecular basis of differential organ growth in mammals. Opossum limbs are an ideal system with which to study differential growth. Opossum forelimbs grow much faster than hind limbs, resulting in newborns with large, well-developed forelimbs that are twice the size of their small, undeveloped hind limbs. Opossum fore- and hind limbs are also serially homologous structures, which ancestrally shared a common developmental program. I first leveraged the great differences in opossum fore- and hind limb growth to identify cellular processes (e.g., proliferation, death, focal adhesions), and the source of the molecular signals (i.e., internal or external to the limb) that drive them, that underlie differential limb growth (Chapter 1). I then elucidated the role of the Fgf/MAPK signaling pathway in driving these cellular processes (Chapter 2). Results suggest that molecular signals from within the limb drive differences in cell proliferation and focal adhesion that contribute to the differential growth of the fore- and hind limbs of M. domestica (Chapter 1). Results also suggest that alterations in the Fgf/Mapk pathway are capable of generating differences in cell proliferation that mirror those observed between wild-type fore- and hind limbs of M. domestica, and that manipulation of Fgf/Mapk signaling affects FA but not Wnt signaling in M. domestica limbs (Chapter 2). Taken together, these findings suggest that evolutionary changes in the Fgf/MAPK pathway could be driving the observed differences in cell behaviors in M. domestica fore- and hind limbs through the FA-ECM pathway (i.e., adhesion). However, these findings also suggest that the evolutionary divergence that led to the differential expression of the Wnt pathway in the limbs of M. domestica likely occurred independently. The findings of this thesis advance our understanding of the regulation of differential limb, and, thereby, organ growth in mammals. Because of the importance of differential organ growth to organismal development, evolution, and health, these findings have the potential to positively impact diverse areas of biological research.
Issue Date:2014-05-30
Rights Information:Copyright 2014 Anna Dowling
Date Available in IDEALS:2014-05-30
Date Deposited:2014-05

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