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Title: The Role of Cell Cycle-Related Kinase (CCRK) in Cellular Proliferation, Ciliogenesis & Central Nervous System Development
Authors: Brown, Desmond Alladin
Advisors: Eggenschwiler, Jonathan T
Contributors: Molecular Biology Department
Keywords: BROMI
mouse development
Neural Patterning
Sonic Hedgehog
Subjects: Molecular biology
Developmental biology
Issue Date: 2012
Publisher: Princeton, NJ : Princeton University
Abstract: <bold> ABSTRACT<bold/> The Sonic hedgehog (Shh) signaling pathway plays a central role in vertebrate development including the proliferation and differentiation of neural stem and progenitor pools and the pathway remains important throughout life. In fact, it has been estimated that misregulation of Shh signaling is a feature of almost a quarter of all human tumors. One interesting aspect of Shh signaling in vertebrates is the dependence on primary cilia, an organelle that only recently was considered vestigial. Recently, cilia have attained prominence as the source of a rather heterogeneous group of diseases (collectively termed ciliopathies) characterized by defects in cilia. Here I provide evidence that cell cycle-related kinase (CCRK) is a novel regulator of Shh signaling through its regulation of primary cilia morphology and function. I also evaluate the ciliary defect in one hereditary ciliopathy, Cranioectodermal Dysplasia (CED), in which there is loss of the intraflagellar transport protein IFT122. Through a series of experiments using techniques in genetics, molecular biology, cell biology and biochemistry, I demonstrate that Ccrk is required during development and that genetic disruption of Ccrk is incompatible with life. Ccrk mutants have short, bulbous cilia which are functionally defective. I show that while canonical Shh pathway components are able to localize to these primary cilia, they do so with much slower dynamics. Consistent with this, Ccrk function is required for maximal activation of Shh signaling and neural patterning in the mouse ventral neural tube. I argue that the observed phenotype is due to the role of Ccrk in the function of primary cilia. Such a role is consistent with epistasis experiments placing Ccrk downstream in the Shh pathway; loss of Ccrk is epistatic to loss of RAB23-a negative regulator of Hedgehog signaling. This work has provided further genetic evidence for the requirement of functional cilia in Shh signaling and suggests a mechanism for how defective cilia may result in reduced Shh signaling. Furthermore, the study characterizes the role of a potential therapeutic target in the form of a "druggable" cytoplasmic kinase. As Shh signaling remains important throughout life, therapeutics capable of attenuating but not completely disrupting Shh signaling may find unparalleled utility.
Alternate format: The Mudd Manuscript Library retains one bound copy of each dissertation. Search for these copies in the library's main catalog
Type of Material: Academic dissertations (Ph.D.)
Language: en
Appears in Collections:Molecular Biology

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