TitleRegulation of TGFβ signaling by microRNAs
NameLi, Ying (author), Irvine, Kenneth (chair), Mckim, Kim (internal member), Driscoll, Monica (internal member), Padgett, Richard (internal member), Kramer, Sunita (outside member), Rutgers University, Graduate School - New Brunswick,
SubjectCell and Developmental Biology,
DescriptionThe TGFβ superfamily plays important roles in various processes. With the genetic tools available, Drosophila has been a useful model organism to study the regulators of the TGFβ pathways, which can shed light on potential treatments for many developmental disorders and diseases caused by aberrant TGFβ signaling. microRNAs (miRNAs) are small non-coding RNAs, acting posttranscriptionally to regulate gene expression, that are involved in various aspects of cellular and developmental processes. My thesis work examines the regulation of TGFβ-like pathways by miRNAs. Specifically, with the combination of computational algorithms and tissue culture methods, my early work successfully identified and validated the targets of Drosophila miRNAs. From that, I found that bantam, a miRNA, can down regulate Mad (Mothers against dpp), a signaling component of TGFβ. Furthermore, I used Drosophila as a model and demonstrated that bantam is a negative regulator of the Dpp (decapentaplegic) pathway. My results showed bantam down regulates Mad (Mothers against dpp) expression in vivo by targeting the Mad 3’UTR, resulting in changes in Dpp signaling. The removal of bantam binding sites in the 3’UTR of a Mad transgene results in a significant increase in the viability of haploinsufficient dpp animals compared to a Mad transgene carrying intact bantam binding sites in the 3’UTR. Interestingly, bantam is up-regulated by Dpp in the wing imaginal disc, and thereby functions in a Dpp feedback loop. Furthermore, this feedback loop is important for maintaining anterior-posterior (A/P) compartment boundary stability in the wing disc through regulation of omb (optomotor-blind). Comparative genomics reveal that bantam is evolutionarily conserved, and miRNA target predictions suggest that human bantam homologs selectively target Smad5, one of two homologs of Mad in BMP signaling, but does not target Smad2 which functions in the activin/TGFβ pathway. These data suggest that bantam is a conserved negative regulator of BMP/Dpp signaling. In addition to the work in the wing disc, I extended my studies and examined the role of bantam in Drosophila brain development. My work shows that bantam is critical for maintaining the stem cell pools of the optic lobe, and that bantam has a cell-autonomously effect on glial cell proliferation and distribution, largely through targeting omb.
NoteIncludes bibliographical references
Noteby Ying Li
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.