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Regulation of Ligand-Mediated Notch Activation in Mammalian Development and Homeostasis

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2014, Doctor of Philosophy, Ohio State University, Molecular Genetics.
The Notch signaling pathway is a cell-to-cell signal transduction mechanism utilized throughout the kingdom metazoa. While we have a strong understanding of the mechanism by which Notch mediates intercellular communication, a growing roster of molecules able to modulate the activity of the Notch pathway represents an area of ongoing investigation. The Delta-like 1 homologue (Dlk1) is a maternally imprinted, alternatively spliced, atypical Notch ligand thought to have important roles in embryonic growth and differentiation. Despite numerous investigations examining the mechanisms by which Dlk1 mediates differentiation in vitro, the in vivo roles for Dlk1 have proven difficult to study. One proposed explanation for this is a requirement for multiple Dlk1 isoforms in DLK1-mediated Notch signaling. To this end, we undertook an examination of the early embryonic expression pattern of all known Dlk1 transcript slice variants. We identified novel expression domains at early developmental stages that suggest a more complex role for multiple Dlk1 splice variants than previously suggested. The Notch pathway is used reiteratively throughout cardiovascular development and maintenance. Perturbed Notch signaling leads to arterial/venous malformations, cardiac disorders, and adult-onset stroke disorder. The reiterative use and complex expression of various components of the Notch pathway in cardiovascular development and maintenance indicates a need for tight regulation of Notch activity throughout the vascular system. A lack of studies directly examining regulation of ligand-mediated Notch activation represents a significant gap in our understanding of the role of Notch signaling in this context. We identify a novel role for the Radical fringe (Rfng) gene, a known modulator of Notch activity, in vascular smooth muscle cell differentiation. Our qPCR analysis shows that Rfng is expressed multiple vascular support cell types. Loss of Rfng function leads to perturbed vascular smooth muscle cell maturation in retinal blood vessels. We examined Notch3-/-; Rfng-/- compound mutant retinal blood vessels, and found Notch3 functions in some aspects of vSMC function independently of Rfng activity. Overall, these findings suggest that the role of Rfng may be more important in vSMC differentiation or maturation than in maintenance. This work provides the first evidence in support of a model in which Rfng modulates the activity of Notch receptors necessary for proper vSMC development and homoeostasis. Future work in the lab will investigate the molecular relationship between RFNG and the NOTCH2 and NOTCH3 receptors.
Susan Cole, Ph.D. (Advisor)
Mark Seeger, Ph.D. (Committee Member)
Brenda Lilly, Ph.D. (Committee Member)
Michael Ostrowski, Ph.D. (Committee Member)
116 p.

Recommended Citations

Citations

  • Miller, A. J. (2014). Regulation of Ligand-Mediated Notch Activation in Mammalian Development and Homeostasis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1420667621

    APA Style (7th edition)

  • Miller, Antony. Regulation of Ligand-Mediated Notch Activation in Mammalian Development and Homeostasis. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1420667621.

    MLA Style (8th edition)

  • Miller, Antony. "Regulation of Ligand-Mediated Notch Activation in Mammalian Development and Homeostasis." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1420667621

    Chicago Manual of Style (17th edition)