ingest cdrApp 2018-03-15T17:11:28.736Z d591f2cd-3da7-4b31-9dd8-ee27dcb6a3ee modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-03-15T17:12:34.986Z Setting exclusive relation addDatastream MD_TECHNICAL fedoraAdmin 2018-03-15T17:12:46.135Z Adding technical metadata derived by FITS addDatastream MD_FULL_TEXT fedoraAdmin 2018-03-15T17:13:11.742Z Adding full text metadata extracted by Apache Tika modifyDatastreamByValue RELS-EXT fedoraAdmin 2018-03-15T17:13:33.988Z Setting exclusive relation modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-05-16T20:30:59.675Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-10T21:19:35.831Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-07-17T17:31:21.958Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-08T16:57:49.145Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-14T21:33:19.210Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-08-16T17:07:41.288Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-21T14:42:14.301Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-09-26T17:34:50.291Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-10-10T18:03:38.958Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2018-10-11T18:28:51.896Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-02-28T01:52:03.280Z modifyDatastreamByValue MD_DESCRIPTIVE cdrApp 2019-03-19T21:10:37.687Z Kevin Byrd Author Oral and Craniofacial Biomedicine PhD Program School of Dentistry How To Make a Mouth: Oral Epithelia Require Locoregional Mitotic Diversity in Morphogenesis and in Maintenace Oral epithelia (OE) frequently renew and function to protect the oral cavity against constant challenge from microbes, toxins, and injury. Despite increasing evidence that differentiation pathways are frequently mutated in oral squamous cell carcinomas (OSCCs), little is known about what regulates OE development and maintenance. Work from our lab in skin has shown that proper orientation of mitotic spindles (oriented cell divisions, OCDs) is essential for development; yet, whether OCDs play any role in OE is unknown. The first aim was to characterize OE development to assess if known OCD gene LGN (Gpsm2) promoted OCDs in OE. Apically localized LGN was found to direct perpendicular divisions that promoted E16.5 OE stratification. Surprisingly, in dorsal tongue (DT), LGN was alternatively localized and promoted planar OCDs. Loss of LGN disrupted the 3D morphogenesis of DT filiform papillae but was dispensable for hair folliculogenesis. Thus, LGN demonstrated tissue-specific functions in ectoderm and its appendage development by spatiotemporally controlling OCDs. The next aim was to assess adult OE under homeostatic conditions, searching for evidence of OE stem/progenitor cell (OESC) heterogeneity. I adopted lineage tracing and genetic label retention strategies, which identified frequently and infrequently dividing cells (FDC/IDCs) in the hard palate. Using lineage tracing, I found evidence of FDCs that often oriented their divisions perpendicularly. However, using label retention assays, I also identified IDCs with characteristics indicative of stemness, including less proliferation and more planar OCDs. With these initial experiments, I provided preliminary evidence of OESC heterogeneity in adult OE, including slower-cycling reserve OESCs and more rapidly dividing active OESCs. The final aim was to test the role of OCDs in oral tumorigenesis. This project aim was to create a novel mouse model of OSCC, LSL-p53R172H or LSL-p53R270H mice, which express p53 gain-on-function “hotspot” mutations (p53GOF) when crossed to an epithelial-specific cre (K14-cre). To accomplish this goal, a large pilot study was performed and demonstrated significantly decreased oral tumor latency in both K14-p53GOF compared to p53WT or heterozygous p53GOF mice. This aim has generated a new model of OSCC that will be used for testing the role of OCDs during OSCC initiation. Winter 2017 2018 Cellular biology Developmental biology Dentistry Cancer, Cell fate, Development, Oral epithelia, Oriented cell division, Tongue eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Dentistry (Oral and Craniofacial Biomedicine) Scott Williams Thesis advisor Eric Everett Thesis advisor Susan Henning Thesis advisor Joan Taylor Thesis advisor Scott Magness Thesis advisor text Kevin Byrd Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry How To Make a Mouth: Oral Epithelia Require Locoregional Mitotic Diversity in Morphogenesis and in Maintenace Oral epithelia (OE) frequently renew and function to protect the oral cavity against constant challenge from microbes, toxins, and injury. Despite increasing evidence that differentiation pathways are frequently mutated in oral squamous cell carcinomas (OSCCs), little is known about what regulates OE development and maintenance. Work from our lab in skin has shown that proper orientation of mitotic spindles (oriented cell divisions, OCDs) is essential for development; yet, whether OCDs play any role in OE is unknown. The first aim was to characterize OE development to assess if known OCD gene LGN (Gpsm2) promoted OCDs in OE. Apically localized LGN was found to direct perpendicular divisions that promoted E16.5 OE stratification. Surprisingly, in dorsal tongue (DT), LGN was alternatively localized and promoted planar OCDs. Loss of LGN disrupted the 3D morphogenesis of DT filiform papillae but was dispensable for hair folliculogenesis. Thus, LGN demonstrated tissue-specific functions in ectoderm and its appendage development by spatiotemporally controlling OCDs. The next aim was to assess adult OE under homeostatic conditions, searching for evidence of OE stem/progenitor cell (OESC) heterogeneity. I adopted lineage tracing and genetic label retention strategies, which identified frequently and infrequently dividing cells (FDC/IDCs) in the hard palate. Using lineage tracing, I found evidence of FDCs that often oriented their divisions perpendicularly. However, using label retention assays, I also identified IDCs with characteristics indicative of stemness, including less proliferation and more planar OCDs. With these initial experiments, I provided preliminary evidence of OESC heterogeneity in adult OE, including slower-cycling reserve OESCs and more rapidly dividing active OESCs. The final aim was to test the role of OCDs in oral tumorigenesis. This project aim was to create a novel mouse model of OSCC, LSL-p53R172H or LSL-p53R270H mice, which express p53 gain-on-function “hotspot” mutations (p53GOF) when crossed to an epithelial-specific cre (K14-cre). To accomplish this goal, a large pilot study was performed and demonstrated significantly decreased oral tumor latency in both K14-p53GOF compared to p53WT or heterozygous p53GOF mice. This aim has generated a new model of OSCC that will be used for testing the role of OCDs during OSCC initiation. 2018 2017 Cellular biology Developmental biology Dentistry Cancer, Cell fate, Development, Oral epithelia, Oriented cell division, Tongue eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Dentistry (Oral and Craniofacial Biomedicine) Scott Williams Thesis advisor Eric Everett Thesis advisor Susan Henning Thesis advisor Joan Taylor Thesis advisor Scott Magness Thesis advisor text Kevin Byrd Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry How To Make a Mouth: Oral Epithelia Require Locoregional Mitotic Diversity in Morphogenesis and in Maintenace Oral epithelia (OE) frequently renew and function to protect the oral cavity against constant challenge from microbes, toxins, and injury. Despite increasing evidence that differentiation pathways are frequently mutated in oral squamous cell carcinomas (OSCCs), little is known about what regulates OE development and maintenance. Work from our lab in skin has shown that proper orientation of mitotic spindles (oriented cell divisions, OCDs) is essential for development; yet, whether OCDs play any role in OE is unknown. The first aim was to characterize OE development to assess if known OCD gene LGN (Gpsm2) promoted OCDs in OE. Apically localized LGN was found to direct perpendicular divisions that promoted E16.5 OE stratification. Surprisingly, in dorsal tongue (DT), LGN was alternatively localized and promoted planar OCDs. Loss of LGN disrupted the 3D morphogenesis of DT filiform papillae but was dispensable for hair folliculogenesis. Thus, LGN demonstrated tissue-specific functions in ectoderm and its appendage development by spatiotemporally controlling OCDs. The next aim was to assess adult OE under homeostatic conditions, searching for evidence of OE stem/progenitor cell (OESC) heterogeneity. I adopted lineage tracing and genetic label retention strategies, which identified frequently and infrequently dividing cells (FDC/IDCs) in the hard palate. Using lineage tracing, I found evidence of FDCs that often oriented their divisions perpendicularly. However, using label retention assays, I also identified IDCs with characteristics indicative of stemness, including less proliferation and more planar OCDs. With these initial experiments, I provided preliminary evidence of OESC heterogeneity in adult OE, including slower-cycling reserve OESCs and more rapidly dividing active OESCs. The final aim was to test the role of OCDs in oral tumorigenesis. This project aim was to create a novel mouse model of OSCC, LSL-p53R172H or LSL-p53R270H mice, which express p53 gain-on-function “hotspot” mutations (p53GOF) when crossed to an epithelial-specific cre (K14-cre). To accomplish this goal, a large pilot study was performed and demonstrated significantly decreased oral tumor latency in both K14-p53GOF compared to p53WT or heterozygous p53GOF mice. This aim has generated a new model of OSCC that will be used for testing the role of OCDs during OSCC initiation. 2018 2017 Cellular biology Developmental biology Dentistry Cancer, Cell fate, Development, Oral epithelia, Oriented cell division, Tongue eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Dentistry (Oral and Craniofacial Biomedicine) Scott Williams Thesis advisor Eric Everett Thesis advisor Susan Henning Thesis advisor Joan Taylor Thesis advisor Scott Magness Thesis advisor text Kevin Byrd Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry How To Make a Mouth: Oral Epithelia Require Locoregional Mitotic Diversity in Morphogenesis and in Maintenace Oral epithelia (OE) frequently renew and function to protect the oral cavity against constant challenge from microbes, toxins, and injury. Despite increasing evidence that differentiation pathways are frequently mutated in oral squamous cell carcinomas (OSCCs), little is known about what regulates OE development and maintenance. Work from our lab in skin has shown that proper orientation of mitotic spindles (oriented cell divisions, OCDs) is essential for development; yet, whether OCDs play any role in OE is unknown. The first aim was to characterize OE development to assess if known OCD gene LGN (Gpsm2) promoted OCDs in OE. Apically localized LGN was found to direct perpendicular divisions that promoted E16.5 OE stratification. Surprisingly, in dorsal tongue (DT), LGN was alternatively localized and promoted planar OCDs. Loss of LGN disrupted the 3D morphogenesis of DT filiform papillae but was dispensable for hair folliculogenesis. Thus, LGN demonstrated tissue-specific functions in ectoderm and its appendage development by spatiotemporally controlling OCDs. The next aim was to assess adult OE under homeostatic conditions, searching for evidence of OE stem/progenitor cell (OESC) heterogeneity. I adopted lineage tracing and genetic label retention strategies, which identified frequently and infrequently dividing cells (FDC/IDCs) in the hard palate. Using lineage tracing, I found evidence of FDCs that often oriented their divisions perpendicularly. However, using label retention assays, I also identified IDCs with characteristics indicative of stemness, including less proliferation and more planar OCDs. With these initial experiments, I provided preliminary evidence of OESC heterogeneity in adult OE, including slower-cycling reserve OESCs and more rapidly dividing active OESCs. The final aim was to test the role of OCDs in oral tumorigenesis. This project aim was to create a novel mouse model of OSCC, LSL-p53R172H or LSL-p53R270H mice, which express p53 gain-on-function “hotspot” mutations (p53GOF) when crossed to an epithelial-specific cre (K14-cre). To accomplish this goal, a large pilot study was performed and demonstrated significantly decreased oral tumor latency in both K14-p53GOF compared to p53WT or heterozygous p53GOF mice. This aim has generated a new model of OSCC that will be used for testing the role of OCDs during OSCC initiation. 2018 2017 Cellular biology Developmental biology Dentistry Cancer, Cell fate, Development, Oral epithelia, Oriented cell division, Tongue eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Dentistry (Oral and Craniofacial Biomedicine) Scott Williams Thesis advisor Eric Everett Thesis advisor Susan Henning Thesis advisor Joan Taylor Thesis advisor Scott Magness Thesis advisor text Kevin Byrd Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry How To Make a Mouth: Oral Epithelia Require Locoregional Mitotic Diversity in Morphogenesis and in Maintenace Oral epithelia (OE) frequently renew and function to protect the oral cavity against constant challenge from microbes, toxins, and injury. Despite increasing evidence that differentiation pathways are frequently mutated in oral squamous cell carcinomas (OSCCs), little is known about what regulates OE development and maintenance. Work from our lab in skin has shown that proper orientation of mitotic spindles (oriented cell divisions, OCDs) is essential for development; yet, whether OCDs play any role in OE is unknown. The first aim was to characterize OE development to assess if known OCD gene LGN (Gpsm2) promoted OCDs in OE. Apically localized LGN was found to direct perpendicular divisions that promoted E16.5 OE stratification. Surprisingly, in dorsal tongue (DT), LGN was alternatively localized and promoted planar OCDs. Loss of LGN disrupted the 3D morphogenesis of DT filiform papillae but was dispensable for hair folliculogenesis. Thus, LGN demonstrated tissue-specific functions in ectoderm and its appendage development by spatiotemporally controlling OCDs. The next aim was to assess adult OE under homeostatic conditions, searching for evidence of OE stem/progenitor cell (OESC) heterogeneity. I adopted lineage tracing and genetic label retention strategies, which identified frequently and infrequently dividing cells (FDC/IDCs) in the hard palate. Using lineage tracing, I found evidence of FDCs that often oriented their divisions perpendicularly. However, using label retention assays, I also identified IDCs with characteristics indicative of stemness, including less proliferation and more planar OCDs. With these initial experiments, I provided preliminary evidence of OESC heterogeneity in adult OE, including slower-cycling reserve OESCs and more rapidly dividing active OESCs. The final aim was to test the role of OCDs in oral tumorigenesis. This project aim was to create a novel mouse model of OSCC, LSL-p53R172H or LSL-p53R270H mice, which express p53 gain-on-function “hotspot” mutations (p53GOF) when crossed to an epithelial-specific cre (K14-cre). To accomplish this goal, a large pilot study was performed and demonstrated significantly decreased oral tumor latency in both K14-p53GOF compared to p53WT or heterozygous p53GOF mice. This aim has generated a new model of OSCC that will be used for testing the role of OCDs during OSCC initiation. 2018 2017 Cellular biology Developmental biology Dentistry Cancer, Cell fate, Development, Oral epithelia, Oriented cell division, Tongue eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Dentistry (Oral and Craniofacial Biomedicine) Scott Williams Thesis advisor Eric Everett Thesis advisor Susan Henning Thesis advisor Joan Taylor Thesis advisor Scott Magness Thesis advisor text Kevin Byrd Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry How To Make a Mouth: Oral Epithelia Require Locoregional Mitotic Diversity in Morphogenesis and in Maintenace Oral epithelia (OE) frequently renew and function to protect the oral cavity against constant challenge from microbes, toxins, and injury. Despite increasing evidence that differentiation pathways are frequently mutated in oral squamous cell carcinomas (OSCCs), little is known about what regulates OE development and maintenance. Work from our lab in skin has shown that proper orientation of mitotic spindles (oriented cell divisions, OCDs) is essential for development; yet, whether OCDs play any role in OE is unknown. The first aim was to characterize OE development to assess if known OCD gene LGN (Gpsm2) promoted OCDs in OE. Apically localized LGN was found to direct perpendicular divisions that promoted E16.5 OE stratification. Surprisingly, in dorsal tongue (DT), LGN was alternatively localized and promoted planar OCDs. Loss of LGN disrupted the 3D morphogenesis of DT filiform papillae but was dispensable for hair folliculogenesis. Thus, LGN demonstrated tissue-specific functions in ectoderm and its appendage development by spatiotemporally controlling OCDs. The next aim was to assess adult OE under homeostatic conditions, searching for evidence of OE stem/progenitor cell (OESC) heterogeneity. I adopted lineage tracing and genetic label retention strategies, which identified frequently and infrequently dividing cells (FDC/IDCs) in the hard palate. Using lineage tracing, I found evidence of FDCs that often oriented their divisions perpendicularly. However, using label retention assays, I also identified IDCs with characteristics indicative of stemness, including less proliferation and more planar OCDs. With these initial experiments, I provided preliminary evidence of OESC heterogeneity in adult OE, including slower-cycling reserve OESCs and more rapidly dividing active OESCs. The final aim was to test the role of OCDs in oral tumorigenesis. This project aim was to create a novel mouse model of OSCC, LSL-p53R172H or LSL-p53R270H mice, which express p53 gain-on-function “hotspot” mutations (p53GOF) when crossed to an epithelial-specific cre (K14-cre). To accomplish this goal, a large pilot study was performed and demonstrated significantly decreased oral tumor latency in both K14-p53GOF compared to p53WT or heterozygous p53GOF mice. This aim has generated a new model of OSCC that will be used for testing the role of OCDs during OSCC initiation. 2018 2017 Cellular biology Developmental biology Dentistry Cancer, Cell fate, Development, Oral epithelia, Oriented cell division, Tongue eng Doctor of Philosophy Dissertation Dentistry (Oral and Craniofacial Biomedicine) Scott Williams Thesis advisor Eric Everett Thesis advisor Susan Henning Thesis advisor Joan Taylor Thesis advisor Scott Magness Thesis advisor text University of North Carolina at Chapel Hill Degree granting institution Kevin Byrd Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry How To Make a Mouth: Oral Epithelia Require Locoregional Mitotic Diversity in Morphogenesis and in Maintenace Oral epithelia (OE) frequently renew and function to protect the oral cavity against constant challenge from microbes, toxins, and injury. Despite increasing evidence that differentiation pathways are frequently mutated in oral squamous cell carcinomas (OSCCs), little is known about what regulates OE development and maintenance. Work from our lab in skin has shown that proper orientation of mitotic spindles (oriented cell divisions, OCDs) is essential for development; yet, whether OCDs play any role in OE is unknown. The first aim was to characterize OE development to assess if known OCD gene LGN (Gpsm2) promoted OCDs in OE. Apically localized LGN was found to direct perpendicular divisions that promoted E16.5 OE stratification. Surprisingly, in dorsal tongue (DT), LGN was alternatively localized and promoted planar OCDs. Loss of LGN disrupted the 3D morphogenesis of DT filiform papillae but was dispensable for hair folliculogenesis. Thus, LGN demonstrated tissue-specific functions in ectoderm and its appendage development by spatiotemporally controlling OCDs. The next aim was to assess adult OE under homeostatic conditions, searching for evidence of OE stem/progenitor cell (OESC) heterogeneity. I adopted lineage tracing and genetic label retention strategies, which identified frequently and infrequently dividing cells (FDC/IDCs) in the hard palate. Using lineage tracing, I found evidence of FDCs that often oriented their divisions perpendicularly. However, using label retention assays, I also identified IDCs with characteristics indicative of stemness, including less proliferation and more planar OCDs. With these initial experiments, I provided preliminary evidence of OESC heterogeneity in adult OE, including slower-cycling reserve OESCs and more rapidly dividing active OESCs. The final aim was to test the role of OCDs in oral tumorigenesis. This project aim was to create a novel mouse model of OSCC, LSL-p53R172H or LSL-p53R270H mice, which express p53 gain-on-function “hotspot” mutations (p53GOF) when crossed to an epithelial-specific cre (K14-cre). To accomplish this goal, a large pilot study was performed and demonstrated significantly decreased oral tumor latency in both K14-p53GOF compared to p53WT or heterozygous p53GOF mice. This aim has generated a new model of OSCC that will be used for testing the role of OCDs during OSCC initiation. 2018 2017 Cellular biology Developmental biology Dentistry Cancer, Cell fate, Development, Oral epithelia, Oriented cell division, Tongue eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Dentistry (Oral and Craniofacial Biomedicine) Scott Williams Thesis advisor Eric Everett Thesis advisor Susan Henning Thesis advisor Joan Taylor Thesis advisor Scott Magness Thesis advisor text Kevin Byrd Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry How To Make a Mouth: Oral Epithelia Require Locoregional Mitotic Diversity in Morphogenesis and in Maintenace Oral epithelia (OE) frequently renew and function to protect the oral cavity against constant challenge from microbes, toxins, and injury. Despite increasing evidence that differentiation pathways are frequently mutated in oral squamous cell carcinomas (OSCCs), little is known about what regulates OE development and maintenance. Work from our lab in skin has shown that proper orientation of mitotic spindles (oriented cell divisions, OCDs) is essential for development; yet, whether OCDs play any role in OE is unknown. The first aim was to characterize OE development to assess if known OCD gene LGN (Gpsm2) promoted OCDs in OE. Apically localized LGN was found to direct perpendicular divisions that promoted E16.5 OE stratification. Surprisingly, in dorsal tongue (DT), LGN was alternatively localized and promoted planar OCDs. Loss of LGN disrupted the 3D morphogenesis of DT filiform papillae but was dispensable for hair folliculogenesis. Thus, LGN demonstrated tissue-specific functions in ectoderm and its appendage development by spatiotemporally controlling OCDs. The next aim was to assess adult OE under homeostatic conditions, searching for evidence of OE stem/progenitor cell (OESC) heterogeneity. I adopted lineage tracing and genetic label retention strategies, which identified frequently and infrequently dividing cells (FDC/IDCs) in the hard palate. Using lineage tracing, I found evidence of FDCs that often oriented their divisions perpendicularly. However, using label retention assays, I also identified IDCs with characteristics indicative of stemness, including less proliferation and more planar OCDs. With these initial experiments, I provided preliminary evidence of OESC heterogeneity in adult OE, including slower-cycling reserve OESCs and more rapidly dividing active OESCs. The final aim was to test the role of OCDs in oral tumorigenesis. This project aim was to create a novel mouse model of OSCC, LSL-p53R172H or LSL-p53R270H mice, which express p53 gain-on-function “hotspot” mutations (p53GOF) when crossed to an epithelial-specific cre (K14-cre). To accomplish this goal, a large pilot study was performed and demonstrated significantly decreased oral tumor latency in both K14-p53GOF compared to p53WT or heterozygous p53GOF mice. This aim has generated a new model of OSCC that will be used for testing the role of OCDs during OSCC initiation. 2018 2017 Cellular biology Developmental biology Dentistry Cancer, Cell fate, Development, Oral epithelia, Oriented cell division, Tongue eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Dentistry (Oral and Craniofacial Biomedicine) Scott Williams Thesis advisor Eric Everett Thesis advisor Susan Henning Thesis advisor Joan Taylor Thesis advisor Scott Magness Thesis advisor text Kevin Byrd Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry How To Make a Mouth: Oral Epithelia Require Locoregional Mitotic Diversity in Morphogenesis and in Maintenace Oral epithelia (OE) frequently renew and function to protect the oral cavity against constant challenge from microbes, toxins, and injury. Despite increasing evidence that differentiation pathways are frequently mutated in oral squamous cell carcinomas (OSCCs), little is known about what regulates OE development and maintenance. Work from our lab in skin has shown that proper orientation of mitotic spindles (oriented cell divisions, OCDs) is essential for development; yet, whether OCDs play any role in OE is unknown. The first aim was to characterize OE development to assess if known OCD gene LGN (Gpsm2) promoted OCDs in OE. Apically localized LGN was found to direct perpendicular divisions that promoted E16.5 OE stratification. Surprisingly, in dorsal tongue (DT), LGN was alternatively localized and promoted planar OCDs. Loss of LGN disrupted the 3D morphogenesis of DT filiform papillae but was dispensable for hair folliculogenesis. Thus, LGN demonstrated tissue-specific functions in ectoderm and its appendage development by spatiotemporally controlling OCDs. The next aim was to assess adult OE under homeostatic conditions, searching for evidence of OE stem/progenitor cell (OESC) heterogeneity. I adopted lineage tracing and genetic label retention strategies, which identified frequently and infrequently dividing cells (FDC/IDCs) in the hard palate. Using lineage tracing, I found evidence of FDCs that often oriented their divisions perpendicularly. However, using label retention assays, I also identified IDCs with characteristics indicative of stemness, including less proliferation and more planar OCDs. With these initial experiments, I provided preliminary evidence of OESC heterogeneity in adult OE, including slower-cycling reserve OESCs and more rapidly dividing active OESCs. The final aim was to test the role of OCDs in oral tumorigenesis. This project aim was to create a novel mouse model of OSCC, LSL-p53R172H or LSL-p53R270H mice, which express p53 gain-on-function “hotspot” mutations (p53GOF) when crossed to an epithelial-specific cre (K14-cre). To accomplish this goal, a large pilot study was performed and demonstrated significantly decreased oral tumor latency in both K14-p53GOF compared to p53WT or heterozygous p53GOF mice. This aim has generated a new model of OSCC that will be used for testing the role of OCDs during OSCC initiation. 2018 2017 Cellular biology Developmental biology Dentistry Cancer; Cell fate; Development; Oral epithelia; Oriented cell division; Tongue eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Dentistry (Oral and Craniofacial Biomedicine) Scott Williams Thesis advisor Eric Everett Thesis advisor Susan Henning Thesis advisor Joan Taylor Thesis advisor Scott Magness Thesis advisor text Kevin Byrd Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry How To Make a Mouth: Oral Epithelia Require Locoregional Mitotic Diversity in Morphogenesis and in Maintenace Oral epithelia (OE) frequently renew and function to protect the oral cavity against constant challenge from microbes, toxins, and injury. Despite increasing evidence that differentiation pathways are frequently mutated in oral squamous cell carcinomas (OSCCs), little is known about what regulates OE development and maintenance. Work from our lab in skin has shown that proper orientation of mitotic spindles (oriented cell divisions, OCDs) is essential for development; yet, whether OCDs play any role in OE is unknown. The first aim was to characterize OE development to assess if known OCD gene LGN (Gpsm2) promoted OCDs in OE. Apically localized LGN was found to direct perpendicular divisions that promoted E16.5 OE stratification. Surprisingly, in dorsal tongue (DT), LGN was alternatively localized and promoted planar OCDs. Loss of LGN disrupted the 3D morphogenesis of DT filiform papillae but was dispensable for hair folliculogenesis. Thus, LGN demonstrated tissue-specific functions in ectoderm and its appendage development by spatiotemporally controlling OCDs. The next aim was to assess adult OE under homeostatic conditions, searching for evidence of OE stem/progenitor cell (OESC) heterogeneity. I adopted lineage tracing and genetic label retention strategies, which identified frequently and infrequently dividing cells (FDC/IDCs) in the hard palate. Using lineage tracing, I found evidence of FDCs that often oriented their divisions perpendicularly. However, using label retention assays, I also identified IDCs with characteristics indicative of stemness, including less proliferation and more planar OCDs. With these initial experiments, I provided preliminary evidence of OESC heterogeneity in adult OE, including slower-cycling reserve OESCs and more rapidly dividing active OESCs. The final aim was to test the role of OCDs in oral tumorigenesis. This project aim was to create a novel mouse model of OSCC, LSL-p53R172H or LSL-p53R270H mice, which express p53 gain-on-function “hotspot” mutations (p53GOF) when crossed to an epithelial-specific cre (K14-cre). To accomplish this goal, a large pilot study was performed and demonstrated significantly decreased oral tumor latency in both K14-p53GOF compared to p53WT or heterozygous p53GOF mice. This aim has generated a new model of OSCC that will be used for testing the role of OCDs during OSCC initiation. 2018 2017 Cellular biology Developmental biology Dentistry Cancer, Cell fate, Development, Oral epithelia, Oriented cell division, Tongue eng Doctor of Philosophy Dissertation Dentistry (Oral and Craniofacial Biomedicine) Scott Williams Thesis advisor Eric Everett Thesis advisor Susan Henning Thesis advisor Joan Taylor Thesis advisor Scott Magness Thesis advisor text University of North Carolina at Chapel Hill Degree granting institution Kevin Byrd Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry How To Make a Mouth: Oral Epithelia Require Locoregional Mitotic Diversity in Morphogenesis and in Maintenace Oral epithelia (OE) frequently renew and function to protect the oral cavity against constant challenge from microbes, toxins, and injury. Despite increasing evidence that differentiation pathways are frequently mutated in oral squamous cell carcinomas (OSCCs), little is known about what regulates OE development and maintenance. Work from our lab in skin has shown that proper orientation of mitotic spindles (oriented cell divisions, OCDs) is essential for development; yet, whether OCDs play any role in OE is unknown. The first aim was to characterize OE development to assess if known OCD gene LGN (Gpsm2) promoted OCDs in OE. Apically localized LGN was found to direct perpendicular divisions that promoted E16.5 OE stratification. Surprisingly, in dorsal tongue (DT), LGN was alternatively localized and promoted planar OCDs. Loss of LGN disrupted the 3D morphogenesis of DT filiform papillae but was dispensable for hair folliculogenesis. Thus, LGN demonstrated tissue-specific functions in ectoderm and its appendage development by spatiotemporally controlling OCDs. The next aim was to assess adult OE under homeostatic conditions, searching for evidence of OE stem/progenitor cell (OESC) heterogeneity. I adopted lineage tracing and genetic label retention strategies, which identified frequently and infrequently dividing cells (FDC/IDCs) in the hard palate. Using lineage tracing, I found evidence of FDCs that often oriented their divisions perpendicularly. However, using label retention assays, I also identified IDCs with characteristics indicative of stemness, including less proliferation and more planar OCDs. With these initial experiments, I provided preliminary evidence of OESC heterogeneity in adult OE, including slower-cycling reserve OESCs and more rapidly dividing active OESCs. The final aim was to test the role of OCDs in oral tumorigenesis. This project aim was to create a novel mouse model of OSCC, LSL-p53R172H or LSL-p53R270H mice, which express p53 gain-on-function “hotspot” mutations (p53GOF) when crossed to an epithelial-specific cre (K14-cre). To accomplish this goal, a large pilot study was performed and demonstrated significantly decreased oral tumor latency in both K14-p53GOF compared to p53WT or heterozygous p53GOF mice. This aim has generated a new model of OSCC that will be used for testing the role of OCDs during OSCC initiation. 2018 2017 Cellular biology Developmental biology Dentistry Cancer, Cell fate, Development, Oral epithelia, Oriented cell division, Tongue eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Dentistry (Oral and Craniofacial Biomedicine) Scott Williams Thesis advisor Eric Everett Thesis advisor Susan Henning Thesis advisor Joan Taylor Thesis advisor Scott Magness Thesis advisor text Kevin Byrd Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry Oral epithelia (OE) frequently renew and function to protect the oral cavity against constant challenge from microbes, toxins, and injury. Despite increasing evidence that differentiation pathways are frequently mutated in oral squamous cell carcinomas (OSCCs), little is known about what regulates OE development and maintenance. Work from our lab in skin has shown that proper orientation of mitotic spindles (oriented cell divisions, OCDs) is essential for development; yet, whether OCDs play any role in OE is unknown. The first aim was to characterize OE development to assess if known OCD gene LGN (Gpsm2) promoted OCDs in OE. Apically localized LGN was found to direct perpendicular divisions that promoted E16.5 OE stratification. Surprisingly, in dorsal tongue (DT), LGN was alternatively localized and promoted planar OCDs. Loss of LGN disrupted the 3D morphogenesis of DT filiform papillae but was dispensable for hair folliculogenesis. Thus, LGN demonstrated tissue-specific functions in ectoderm and its appendage development by spatiotemporally controlling OCDs. The next aim was to assess adult OE under homeostatic conditions, searching for evidence of OE stem/progenitor cell (OESC) heterogeneity. I adopted lineage tracing and genetic label retention strategies, which identified frequently and infrequently dividing cells (FDC/IDCs) in the hard palate. Using lineage tracing, I found evidence of FDCs that often oriented their divisions perpendicularly. However, using label retention assays, I also identified IDCs with characteristics indicative of stemness, including less proliferation and more planar OCDs. With these initial experiments, I provided preliminary evidence of OESC heterogeneity in adult OE, including slower-cycling reserve OESCs and more rapidly dividing active OESCs. The final aim was to test the role of OCDs in oral tumorigenesis. This project aim was to create a novel mouse model of OSCC, LSL-p53R172H or LSL-p53R270H mice, which express p53 gain-on-function “hotspot” mutations (p53GOF) when crossed to an epithelial-specific cre (K14-cre). To accomplish this goal, a large pilot study was performed and demonstrated significantly decreased oral tumor latency in both K14-p53GOF compared to p53WT or heterozygous p53GOF mice. This aim has generated a new model of OSCC that will be used for testing the role of OCDs during OSCC initiation. 2018 2017 Cellular biology Developmental biology Dentistry Cancer; Cell fate; Development; Oral epithelia; Oriented cell division; Tongue eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Dentistry (Oral and Craniofacial Biomedicine) Scott Williams Thesis advisor Eric Everett Thesis advisor Susan Henning Thesis advisor Joan Taylor Thesis advisor Scott Magness Thesis advisor text Kevin Byrd Creator Oral and Craniofacial Biomedicine PhD Program School of Dentistry Oral epithelia (OE) frequently renew and function to protect the oral cavity against constant challenge from microbes, toxins, and injury. Despite increasing evidence that differentiation pathways are frequently mutated in oral squamous cell carcinomas (OSCCs), little is known about what regulates OE development and maintenance. Work from our lab in skin has shown that proper orientation of mitotic spindles (oriented cell divisions, OCDs) is essential for development; yet, whether OCDs play any role in OE is unknown. The first aim was to characterize OE development to assess if known OCD gene LGN (Gpsm2) promoted OCDs in OE. Apically localized LGN was found to direct perpendicular divisions that promoted E16.5 OE stratification. Surprisingly, in dorsal tongue (DT), LGN was alternatively localized and promoted planar OCDs. Loss of LGN disrupted the 3D morphogenesis of DT filiform papillae but was dispensable for hair folliculogenesis. Thus, LGN demonstrated tissue-specific functions in ectoderm and its appendage development by spatiotemporally controlling OCDs. The next aim was to assess adult OE under homeostatic conditions, searching for evidence of OE stem/progenitor cell (OESC) heterogeneity. I adopted lineage tracing and genetic label retention strategies, which identified frequently and infrequently dividing cells (FDC/IDCs) in the hard palate. Using lineage tracing, I found evidence of FDCs that often oriented their divisions perpendicularly. However, using label retention assays, I also identified IDCs with characteristics indicative of stemness, including less proliferation and more planar OCDs. With these initial experiments, I provided preliminary evidence of OESC heterogeneity in adult OE, including slower-cycling reserve OESCs and more rapidly dividing active OESCs. The final aim was to test the role of OCDs in oral tumorigenesis. This project aim was to create a novel mouse model of OSCC, LSL-p53R172H or LSL-p53R270H mice, which express p53 gain-on-function “hotspot” mutations (p53GOF) when crossed to an epithelial-specific cre (K14-cre). To accomplish this goal, a large pilot study was performed and demonstrated significantly decreased oral tumor latency in both K14-p53GOF compared to p53WT or heterozygous p53GOF mice. This aim has generated a new model of OSCC that will be used for testing the role of OCDs during OSCC initiation. 2018 2017 Cellular biology Developmental biology Dentistry Cancer; Cell fate; Development; Oral epithelia; Oriented cell division; Tongue eng Doctor of Philosophy Dissertation University of North Carolina at Chapel Hill Graduate School Degree granting institution Scott Williams Thesis advisor Eric Everett Thesis advisor Susan Henning Thesis advisor Joan Taylor Thesis advisor Scott Magness Thesis advisor text Byrd_unc_0153D_17449.pdf uuid:92fa76ad-c0a7-44f9-a1d3-6727c5a4a8a4 2020-03-15T00:00:00 2017-12-01T17:43:56Z proquest application/pdf 117144500