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Cell and developmental stage specific role of Dicer1 in the lung epithelium

Gardner, Margaret A, B.S.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427797752

Abstract Details

2015, MS, University of Cincinnati, Medicine: Molecular and Developmental Biology.
microRNAs (miRNAs) are a highly conserved class of small non-coding RNAs that play fundamental roles during both development and disease. Like signaling molecules required for proper lung morphogenesis, miRNAs are dynamically expressed throughout lung development and precise control of their expression is crucial for proper lung organogenesis. Functional miRNA processing relies on DICER1, a critical enzyme required for the final processing step for mature miRNA production, and DICER1 itself has been shown to play fundamental roles in mammalian development. Germline heterozygous loss-of-function DICER1 mutations were found in a majority of patients with the hereditary pediatric lung tumor, pleuropulmonary blastoma (PPB), and full DICER1 loss was seen specifically in the epithelial compartment of PPB. These genetic findings led us to hypothesize that DICER1 loss is sufficient for PPB initiation. To test our hypothesis, we generated conditional mouse models wherein Dicer1 loss was targeted to the developing lung epithelium in order to mimic genetic alterations seen in humans. Epithelial Dicer1 loss resulted in lethality at birth due to a lung phenotype morphologically indistinguishable from human PPB seen in neonates. Additionally, we demonstrated that Dicer1 has temporal and cell type specific functions during lung development. Our models represent unique tools to address multiple facets of Dicer1 function in the developing lung. We show that epithelial Dicer1 loss alone is not sufficient for PPB progression, which is consistent with reports in the literature demonstrating additional mutations in tumors from patients with later stage disease. These added mutations may, in fact, promote PPB progression and our mouse models provide ideal systems for directly testing whether these genetic alterations lead to disease progression. Beyond the context of PPB pathogenesis, our models can be used to study mechanisms underlying Dicer1 dependent regulation in the lung. Preliminary data from our lab demonstrates that expression of molecules critical for epithelial-mesenchymal signaling and proper lung morphogenesis are altered after Dicer1 loss and may be playing roles in Dicer1 dependent phenotypes. Finally, our models can be utilized to study the fate of Dicer1 deficient lung epithelial cells, which has yet to be explored in the literature. Thus, these mouse models provide a powerful means to address the critical roles that Dicer1 plays during mammalian lung development.
Kathryn Wikenheiser-Brokamp, M.D. Ph.D. (Committee Chair)
Brian Gebelein, Ph.D. (Committee Member)
Steven Potter, Ph.D. (Committee Member)
John Shannon, Ph.D. (Committee Member)
70 p.
Developmental Biology
Dicer1; microrna; Pleuropulmonary blastoma; lung development

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Citations

  • Gardner, M. A. (2015). Cell and developmental stage specific role of Dicer1 in the lung epithelium [Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427797752

    APA Style (7th edition)

  • Gardner, Margaret. Cell and developmental stage specific role of Dicer1 in the lung epithelium. 2015. University of Cincinnati, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427797752.

    MLA Style (8th edition)

  • Gardner, Margaret. "Cell and developmental stage specific role of Dicer1 in the lung epithelium." Master's thesis, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1427797752

    Chicago Manual of Style (17th edition)

ucin1427797752
286
© 2015, some rights reserved.Creative Commons License Cell and developmental stage specific role of Dicer1 in the lung epithelium by Margaret A Gardner B.S. is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.