Donald Singer

Abstract

Since its discovery, CD133 has been used to identify, isolate and characterise many different stem cell types across a wide variety of tissues. Nonetheless, to date not much has been elucidated about its function in these cells. The continuously growing mouse incisor contains a large population of epithelial stem cells that drive the constant need for enamel generation. Using this model, this project aims to elucidate the role of CD133 in epithelial stem cell renewal and activation. After validating the presence of CD133 in the developing mouse incisor epithelium, this project compared the dental epithelial stem cell dynamics of wildtype mice versus CD133 KO mice. Mutant mice displayed significant anomalies across the whole dental epithelium, ultimately, leading to defects in the enamel, the product of fully differentiated ameloblasts. Subcellular analysis of the dental incisor epithelium in CD133 KO mice revealed disturbed primary cilia homeostasis. Primary cilia are crucial in interpreting extracellular cues and CD133 KO primary cilia specifically fail to transmit Shh-mediated signals. Further investigation of the functions of CD133 revealed that CD133 is important for the sequential recruitment of Arl13b and Hdac6 to the primary cilium regulating proper ciliogenesis. Establishment of an in vitro cell culture model of dental epithelial cells allowed the investigation of nuclear CD133 under normal physiological conditions. To date, nuclear CD133 has been reported in a variety of cancers. This study provides insight into the formation of the CD133-Glis2 complex in the nucleus. This complex regulates the expression of Stat3, an important regulator of stem cells, in the dental epithelium. In summary, this study has elucidated the importance of CD133 on primary cilium homeostasis, which in turn regulates stem cell renewal and activation in the developing incisor epithelium.

Keywords

Stem cell, primary cilium, CD133

Document Type

Thesis

Publication Date

2019

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