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You searched for +publisher:"Temple University" +contributor:("Thomas, Gareth;"). Showing records 1 – 2 of 2 total matches.

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Temple University

1. Hughes, Lucinda Jane. Yes-Associated Protein (YAP) and Transcriptional Co-Activator with PDZ Binding Motif (TAZ) Function in Normal Cerebellar Development and Medulloblastoma.

Degree: PhD, 2016, Temple University

Biomedical Sciences

The Hippo signaling pathway was first discovered in Drosophila melanogaster and is involved in organ size control by regulating cell proliferation and apoptosis. This well conserved pathway is activated by various signal inputs, including cell-cell contact, mechanotransduction, and G-protein coupled receptors, with signals converging on the downstream effector protein Yap and its homologue Taz, which are transcriptional co-activators. When the Hippo pathway is activated, Yap/Taz are phosphorylated, leading to cytoplasmic retention and degradation, and diminishing their transcriptional activity. Yap has also been recently implicated as a potential oncogene, as it is upregulated and transcriptionally active in several tumor types. Furthermore, inhibiting Yap activity in various cancer models has been shown to revert cancer cells to a normal phenotype. Although the role of Yap has been described in several organ systems, there is a paucity of information about the function of Yap in the central nervous system. I investigated the function of Yap/Taz in the murine cerebellum to determine its significance during normal development and a potential role for Yap/Taz in medulloblastoma, a tumor that arises in the cerebellum. In Chapter 2, I describe the expression pattern of Yap from embryonic through adult stages in mice, and demonstrate the functional significance of Yap/Taz in different cell populations using conditional knockout mouse models. I show that Yap plays a significant role in cell fate determination as well as in cerebellar foliation: Yap is highly expressed in the ventricular zone and is required for the proper formation of ependymal cells, and is also strongly expressed in Bergmann glia (BG) during early developmental stages, where Yap, together with Taz, plays a significant role in cerebellar foliation. Furthermore, Yap/Taz-deficient BG exhibit migrational defects, as their cell bodies can be found mislocalized to the molecular layer (ML), rather than remaining tightly associated with Purkinje Cells (PCs) in the PC layer. BG support the health of PCs, and severely defective BG positioning eventually leads to a loss of PCs. However, although Yap is highly expressed in granule neuron progenitors (GNPs) during the rapid postnatal expansion stage, it does not appear to play a major role in proliferation of these cells as conditionally knocking-out Yap/Taz in GNPs does not alter their proliferative capacity. Our observations demonstrate that in the cerebellum, Yap has a novel function in glia that is required for the development of normal foliation and organization, but plays a minimal role in GNP proliferation. Importantly, I also show that the reduction of sphingosine-1-phosphate G-protein-coupled receptor (S1P1) signal transduction activates the upstream kinase Lats with concomitant increases of phosphorylated Yap as well as a reduction of the known Yap target connective tissue growth factor (CTGF). This study identifies a novel function of Yap/Taz in cerebellar glia that is required for…

Advisors/Committee Members: Kim, Seonhee;, Graña, Xavier, Pearson, Helen E., Thomas, Gareth, Shore, Scott K.;.

Subjects/Keywords: Developmental biology; Cellular biology; Neurosciences;

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Hughes, L. J. (2016). Yes-Associated Protein (YAP) and Transcriptional Co-Activator with PDZ Binding Motif (TAZ) Function in Normal Cerebellar Development and Medulloblastoma. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,412035

Chicago Manual of Style (16th Edition):

Hughes, Lucinda Jane. “Yes-Associated Protein (YAP) and Transcriptional Co-Activator with PDZ Binding Motif (TAZ) Function in Normal Cerebellar Development and Medulloblastoma.” 2016. Doctoral Dissertation, Temple University. Accessed September 25, 2020. http://digital.library.temple.edu/u?/p245801coll10,412035.

MLA Handbook (7th Edition):

Hughes, Lucinda Jane. “Yes-Associated Protein (YAP) and Transcriptional Co-Activator with PDZ Binding Motif (TAZ) Function in Normal Cerebellar Development and Medulloblastoma.” 2016. Web. 25 Sep 2020.

Vancouver:

Hughes LJ. Yes-Associated Protein (YAP) and Transcriptional Co-Activator with PDZ Binding Motif (TAZ) Function in Normal Cerebellar Development and Medulloblastoma. [Internet] [Doctoral dissertation]. Temple University; 2016. [cited 2020 Sep 25]. Available from: http://digital.library.temple.edu/u?/p245801coll10,412035.

Council of Science Editors:

Hughes LJ. Yes-Associated Protein (YAP) and Transcriptional Co-Activator with PDZ Binding Motif (TAZ) Function in Normal Cerebellar Development and Medulloblastoma. [Doctoral Dissertation]. Temple University; 2016. Available from: http://digital.library.temple.edu/u?/p245801coll10,412035


Temple University

2. Collura, Kaitlin Marie. Palmitoylation-Dependent Regulation of the DLK/JNK/cJun and the GP130/JAK/STAT Retrograde Signaling Pathways.

Degree: PhD, 2015, Temple University

Biomedical Sciences

Palmitoylation is the post-translational addition of the 16-carbon fatty acid palmitate to protein cysteine residues. This process is best known for its roles in targeting proteins to lipid membranes, including both the plasma membrane and vesicles. Palmitoylation occurs in all eukaryotic cells, but appears to be particularly important in neurons, because genetic mutation or loss of several palmitoyl acyltransferases (PATs, the enzymes that catalyze palmitoylation), leads to predominantly neuropathological defects. In addition, a growing number of recent studies have revealed key roles for palmitoylation of specific proteins in neuronal regulation. However, most of these studies have focused on how palmitoylation regulates postsynaptic protein targeting. In contrast, it is far less clear how palmitoylation might regulate the specialized subcellular processes that are important in axons. One particularly important process in axons is retrograde signaling, in which information is conveyed from distal locations back to the cell body. Following injury to axons of the peripheral nervous system (PNS), retrograde signals are critical to activate transcription of pro-regenerative genes. Key retrograde signaling pathways include the DLK/JNK/c-Jun (Dual Leucine Zipper Kinase/c-Jun N-terminal Kinase/c-Jun) signaling pathway and the GP130/JAK/STAT (Glycoprotein 130/Janus Kinase/Signal Transducer and Activator of Transcription) signaling pathway, both of which are activated following nerve injury and are vital to promote regeneration. Though both of these pathways are critical for conveying distal information from the periphery to the cell body, many of their component proteins are predicted to be soluble and diffusible. This raises the question of how these proteins can directionally signal over the long distances that axons extend. Interestingly, bio-informatic and proteomic studies suggested that DLK, GP130, JAK and STAT may be palmitoylated. We hypothesized that palmitoylation could be important for the roles of these proteins in retrograde signaling. Because retrograde signals are initiated in distal axons, a considerable distance from the cell body, we further hypothesized axonally localized PATs might play key roles in the control of retrograde signaling. We find that the retrograde signaling protein DLK is palmitoylated at a highly conserved cysteine residue. This modification is necessary for its localization to motile vesicles and for its interaction with the retrograde signaling protein JIP3. Notably, we also describe a novel role for palmitoylation in regulating DLK’s kinase activity. In addition, our study identifies the first axonally enriched PATs in sensory neurons; DHHC5 and DHHC8. shRNA knockdown experiments in sensory neurons reveal that these axonal PATs control both palmitoylation and surface expression of GP130 and are essential for GP130/JAK/STAT3-dependent retrograde signaling. These findings reveal a novel role for palmitoylation in the control of axonal retrograde signaling,…

Advisors/Committee Members: Thomas, Gareth;, Soprano, Dianne R., Ramirez, Servio, Son, Young-Jin, Shore, Scott K.;.

Subjects/Keywords: Neurosciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Collura, K. M. (2015). Palmitoylation-Dependent Regulation of the DLK/JNK/cJun and the GP130/JAK/STAT Retrograde Signaling Pathways. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,426710

Chicago Manual of Style (16th Edition):

Collura, Kaitlin Marie. “Palmitoylation-Dependent Regulation of the DLK/JNK/cJun and the GP130/JAK/STAT Retrograde Signaling Pathways.” 2015. Doctoral Dissertation, Temple University. Accessed September 25, 2020. http://digital.library.temple.edu/u?/p245801coll10,426710.

MLA Handbook (7th Edition):

Collura, Kaitlin Marie. “Palmitoylation-Dependent Regulation of the DLK/JNK/cJun and the GP130/JAK/STAT Retrograde Signaling Pathways.” 2015. Web. 25 Sep 2020.

Vancouver:

Collura KM. Palmitoylation-Dependent Regulation of the DLK/JNK/cJun and the GP130/JAK/STAT Retrograde Signaling Pathways. [Internet] [Doctoral dissertation]. Temple University; 2015. [cited 2020 Sep 25]. Available from: http://digital.library.temple.edu/u?/p245801coll10,426710.

Council of Science Editors:

Collura KM. Palmitoylation-Dependent Regulation of the DLK/JNK/cJun and the GP130/JAK/STAT Retrograde Signaling Pathways. [Doctoral Dissertation]. Temple University; 2015. Available from: http://digital.library.temple.edu/u?/p245801coll10,426710

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