{"id":{"repo_id":"ku","oai_identifier":"oai:kuscholarworks.ku.edu:1808/38371"},"canonical_url":"https://search.dev.ndltd.org/etd/ku/oai:kuscholarworks.ku.edu:1808/38371","repository":{"repo_id":"ku","name":"University of Kansas","base_url":"https://kuscholarworks.ku.edu/server/oai/request"},"display":{"title":"The Role of PRICKLE1 in the Regulation of Uterine Structure and Physiology","abstract":"The uterus is a complex organ within the female reproductive system, crucial for reproduction and fertility. The uterus consists of distinct and specialized layers, each playing an important role in supporting uterine functions through intricate interactions. The innermost layer of the uterus, the endometrium, is critical for successful implantation and pregnancy. The smooth muscle cells of the myometrial layer are organized into several sub-layers with longitudinal and circular orientations and help to facilitate uterine contractions and sperm transport. The specific cellular arrangement and orienertaion is crucial for the layer’s function and is regulated by steroid hormones and extracellular matrix (ECM) organization. Under pathological conditions, such as uterine leiomyoma (UL, uterine fibroids), myometrial cell and ECM deposition and organization are disrupted through fibrosis. Despite its importance, the mechanisms governing uterine cell organization, the impact of ECM organization, and uterine fibrosis remain poorly understood. Animal models, including the Eker rat and MED12-mutated mice, provide valuable insights in UL but have significant limitations. Genetic animal models that faithfully represent gene expression changes seen in UL and recapitulate UL phenotype are lacking. Our lab had previously developed two new mouse models: one with overexpressed human GPR10 and another with myometrial-specific Cre to ablate Rest, both showing promising similarities to human UL. These models offer potential for studying the pathogenesis and treatment of UL in vivo. However, there is still a need to develop new and better mouse models that encompass the cellular disorganization seen in human UL. The PRICKLE protein family is integral to non-canonical Wnt/Planar Cell Polarity (PCP) signaling, regulating cell adhesion, migration, and differentiation. Dysregulation of PRICKLE1 is implicated in various diseases, including cancer and epilepsy. In UL, PRICKLE1 is proposed to be essential for REST nuclear localization, with its dysregulation contributing to aberrant gene expression and enhanced PI3K/AKT-mTOR signaling, characteristic of UL. In addition, our lab has linked environmental estrogen exposure to PRICKLE1 dysregulation in UL pathogenesis. PRICKLE1 dysfunction is also associated with MED12 mutations, prevalent in UL, making it an interesting target of investigation for UL. In addition, the endometrial epithelium’s ability to maintain regulated cell division through apical-basal polarity is a key aspect of the menstrual cycle, embryo implantation, and pregnancy. The capacity of the endometrium to undergo these structural changes smoothly is crucial for fertility, yet significant gaps remain, particularly in the context of uterine epithelial morphogenesis and PCP signaling during implantation. Research and animal models to study PCP signaling, specifically the unstudied role of PRICKLE proteins, are crucial for elucidating the molecular mechanisms of uterine receptivity, endometrial structure, and embryo implantation. This dissertation aims to elucidate PRICKLE1's role in uterine physiology, specifically in UL pathogenesis and endometrial structure. Utilizing two novel mouse models, a myometrial-specific cKO (Prickle1f/f MiC) and an endometrial epithelial-specific cKO (Prickle1f/f Ltf+/icre), I hypothesized that the loss of PRICKLE1 in the myometrium leads to a UL phenotype and disrupts PCP in the endometrial epithelium. The findings showed that PRICKLE1 loss in the myometrium resulted in fibrotic structure formation, altered gene expression, and disrupted signaling pathways, mirroring human UL. The loss of PRICKLE1 in the endometrial epithelium caused altered cell division, incomplete cytokinesis, and implantation defects.","abstract_html":"The uterus is a complex organ within the female reproductive system, crucial for reproduction and fertility. The uterus consists of distinct and specialized layers, each playing an important role in supporting uterine functions through intricate interactions. The innermost layer of the uterus, the endometrium, is critical for successful implantation and pregnancy. The smooth muscle cells of the myometrial layer are organized into several sub-layers with longitudinal and circular orientations and help to facilitate uterine contractions and sperm transport. The specific cellular arrangement and orienertaion is crucial for the layer’s function and is regulated by steroid hormones and extracellular matrix (ECM) organization. Under pathological conditions, such as uterine leiomyoma (UL, uterine fibroids), myometrial cell and ECM deposition and organization are disrupted through fibrosis. Despite its importance, the mechanisms governing uterine cell organization, the impact of ECM organization, and uterine fibrosis remain poorly understood. Animal models, including the Eker rat and MED12-mutated mice, provide valuable insights in UL but have significant limitations. Genetic animal models that faithfully represent gene expression changes seen in UL and recapitulate UL phenotype are lacking. Our lab had previously developed two new mouse models: one with overexpressed human GPR10 and another with myometrial-specific Cre to ablate Rest, both showing promising similarities to human UL. These models offer potential for studying the pathogenesis and treatment of UL in vivo. However, there is still a need to develop new and better mouse models that encompass the cellular disorganization seen in human UL. The PRICKLE protein family is integral to non-canonical Wnt/Planar Cell Polarity (PCP) signaling, regulating cell adhesion, migration, and differentiation. Dysregulation of PRICKLE1 is implicated in various diseases, including cancer and epilepsy. In UL, PRICKLE1 is proposed to be essential for REST nuclear localization, with its dysregulation contributing to aberrant gene expression and enhanced PI3K/AKT-mTOR signaling, characteristic of UL. In addition, our lab has linked environmental estrogen exposure to PRICKLE1 dysregulation in UL pathogenesis. PRICKLE1 dysfunction is also associated with MED12 mutations, prevalent in UL, making it an interesting target of investigation for UL. In addition, the endometrial epithelium’s ability to maintain regulated cell division through apical-basal polarity is a key aspect of the menstrual cycle, embryo implantation, and pregnancy. The capacity of the endometrium to undergo these structural changes smoothly is crucial for fertility, yet significant gaps remain, particularly in the context of uterine epithelial morphogenesis and PCP signaling during implantation. Research and animal models to study PCP signaling, specifically the unstudied role of PRICKLE proteins, are crucial for elucidating the molecular mechanisms of uterine receptivity, endometrial structure, and embryo implantation. This dissertation aims to elucidate PRICKLE1's role in uterine physiology, specifically in UL pathogenesis and endometrial structure. Utilizing two novel mouse models, a myometrial-specific cKO (Prickle1f/f MiC) and an endometrial epithelial-specific cKO (Prickle1f/f Ltf+/icre), I hypothesized that the loss of PRICKLE1 in the myometrium leads to a UL phenotype and disrupts PCP in the endometrial epithelium. The findings showed that PRICKLE1 loss in the myometrium resulted in fibrotic structure formation, altered gene expression, and disrupted signaling pathways, mirroring human UL. The loss of PRICKLE1 in the endometrial epithelium caused altered cell division, incomplete cytokinesis, and implantation defects.","abstract_has_math":false,"creators":["Roberts, Emily"],"institution":"University of Kansas","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Chennathukuzhi, Vargheese"],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-01-01","date_published":"2024-01-01","updated_at":"2026-07-24T02:46:29Z","subjects":["Physiology","Endometrial Epithelium","Fibroids","Prickle1","Reproduction","Uterine Leiomyoma","Wnt/Planar Cell Polarity"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["http://dissertations.umi.com/ku:19841"],"render_values":[{"text":"http://dissertations.umi.com/ku:19841","href":"http://dissertations.umi.com/ku:19841","code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/1808/38371","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Chennathukuzhi, Vargheese"]},{"key":"dc:creator","label":"Author","values":["Roberts, Emily"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2026-04-24T01:33:06Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2026-04-24T01:33:06Z"]},{"key":"dc:date.issued","label":"Date","values":["2024-01-01"]},{"key":"dc:publisher","label":"Institution","values":["University of Kansas"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Physiology","Endometrial Epithelium","Fibroids","Prickle1","Reproduction","Uterine Leiomyoma","Wnt/Planar Cell Polarity"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["http://dissertations.umi.com/ku:19841"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1808/38371"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The uterus is a complex organ within the female reproductive system, crucial for reproduction and fertility. The uterus consists of distinct and specialized layers, each playing an important role in supporting uterine functions through intricate interactions. The innermost layer of the uterus, the endometrium, is critical for successful implantation and pregnancy. The smooth muscle cells of the myometrial layer are organized into several sub-layers with longitudinal and circular orientations and help to facilitate uterine contractions and sperm transport. The specific cellular arrangement and orienertaion is crucial for the layer’s function and is regulated by steroid hormones and extracellular matrix (ECM) organization. Under pathological conditions, such as uterine leiomyoma (UL, uterine fibroids), myometrial cell and ECM deposition and organization are disrupted through fibrosis. Despite its importance, the mechanisms governing uterine cell organization, the impact of ECM organization, and uterine fibrosis remain poorly understood. Animal models, including the Eker rat and MED12-mutated mice, provide valuable insights in UL but have significant limitations. Genetic animal models that faithfully represent gene expression changes seen in UL and recapitulate UL phenotype are lacking. Our lab had previously developed two new mouse models: one with overexpressed human GPR10 and another with myometrial-specific Cre to ablate Rest, both showing promising similarities to human UL. These models offer potential for studying the pathogenesis and treatment of UL in vivo. However, there is still a need to develop new and better mouse models that encompass the cellular disorganization seen in human UL. The PRICKLE protein family is integral to non-canonical Wnt/Planar Cell Polarity (PCP) signaling, regulating cell adhesion, migration, and differentiation. Dysregulation of PRICKLE1 is implicated in various diseases, including cancer and epilepsy. In UL, PRICKLE1 is proposed to be essential for REST nuclear localization, with its dysregulation contributing to aberrant gene expression and enhanced PI3K/AKT-mTOR signaling, characteristic of UL. In addition, our lab has linked environmental estrogen exposure to PRICKLE1 dysregulation in UL pathogenesis. PRICKLE1 dysfunction is also associated with MED12 mutations, prevalent in UL, making it an interesting target of investigation for UL. In addition, the endometrial epithelium’s ability to maintain regulated cell division through apical-basal polarity is a key aspect of the menstrual cycle, embryo implantation, and pregnancy. The capacity of the endometrium to undergo these structural changes smoothly is crucial for fertility, yet significant gaps remain, particularly in the context of uterine epithelial morphogenesis and PCP signaling during implantation. Research and animal models to study PCP signaling, specifically the unstudied role of PRICKLE proteins, are crucial for elucidating the molecular mechanisms of uterine receptivity, endometrial structure, and embryo implantation. This dissertation aims to elucidate PRICKLE1's role in uterine physiology, specifically in UL pathogenesis and endometrial structure. Utilizing two novel mouse models, a myometrial-specific cKO (Prickle1f/f MiC) and an endometrial epithelial-specific cKO (Prickle1f/f Ltf+/icre), I hypothesized that the loss of PRICKLE1 in the myometrium leads to a UL phenotype and disrupts PCP in the endometrial epithelium. The findings showed that PRICKLE1 loss in the myometrium resulted in fibrotic structure formation, altered gene expression, and disrupted signaling pathways, mirroring human UL. The loss of PRICKLE1 in the endometrial epithelium caused altered cell division, incomplete cytokinesis, and implantation defects."]},{"key":"dc:title","label":"Title","values":["The Role of PRICKLE1 in the Regulation of Uterine Structure and Physiology"]}]}],"canonical_facts":{"dc:contributor.advisor":["Chennathukuzhi, Vargheese"],"dc:creator":["Roberts, Emily"],"dc:date.accessioned":["2026-04-24T01:33:06Z"],"dc:date.available":["2026-04-24T01:33:06Z"],"dc:date.issued":["2024-01-01"],"dc:description.abstract":["The uterus is a complex organ within the female reproductive system, crucial for reproduction and fertility. The uterus consists of distinct and specialized layers, each playing an important role in supporting uterine functions through intricate interactions. The innermost layer of the uterus, the endometrium, is critical for successful implantation and pregnancy. The smooth muscle cells of the myometrial layer are organized into several sub-layers with longitudinal and circular orientations and help to facilitate uterine contractions and sperm transport. The specific cellular arrangement and orienertaion is crucial for the layer’s function and is regulated by steroid hormones and extracellular matrix (ECM) organization. Under pathological conditions, such as uterine leiomyoma (UL, uterine fibroids), myometrial cell and ECM deposition and organization are disrupted through fibrosis. Despite its importance, the mechanisms governing uterine cell organization, the impact of ECM organization, and uterine fibrosis remain poorly understood. Animal models, including the Eker rat and MED12-mutated mice, provide valuable insights in UL but have significant limitations. Genetic animal models that faithfully represent gene expression changes seen in UL and recapitulate UL phenotype are lacking. Our lab had previously developed two new mouse models: one with overexpressed human GPR10 and another with myometrial-specific Cre to ablate Rest, both showing promising similarities to human UL. These models offer potential for studying the pathogenesis and treatment of UL in vivo. However, there is still a need to develop new and better mouse models that encompass the cellular disorganization seen in human UL. The PRICKLE protein family is integral to non-canonical Wnt/Planar Cell Polarity (PCP) signaling, regulating cell adhesion, migration, and differentiation. Dysregulation of PRICKLE1 is implicated in various diseases, including cancer and epilepsy. In UL, PRICKLE1 is proposed to be essential for REST nuclear localization, with its dysregulation contributing to aberrant gene expression and enhanced PI3K/AKT-mTOR signaling, characteristic of UL. In addition, our lab has linked environmental estrogen exposure to PRICKLE1 dysregulation in UL pathogenesis. PRICKLE1 dysfunction is also associated with MED12 mutations, prevalent in UL, making it an interesting target of investigation for UL. In addition, the endometrial epithelium’s ability to maintain regulated cell division through apical-basal polarity is a key aspect of the menstrual cycle, embryo implantation, and pregnancy. The capacity of the endometrium to undergo these structural changes smoothly is crucial for fertility, yet significant gaps remain, particularly in the context of uterine epithelial morphogenesis and PCP signaling during implantation. Research and animal models to study PCP signaling, specifically the unstudied role of PRICKLE proteins, are crucial for elucidating the molecular mechanisms of uterine receptivity, endometrial structure, and embryo implantation. This dissertation aims to elucidate PRICKLE1's role in uterine physiology, specifically in UL pathogenesis and endometrial structure. Utilizing two novel mouse models, a myometrial-specific cKO (Prickle1f/f MiC) and an endometrial epithelial-specific cKO (Prickle1f/f Ltf+/icre), I hypothesized that the loss of PRICKLE1 in the myometrium leads to a UL phenotype and disrupts PCP in the endometrial epithelium. The findings showed that PRICKLE1 loss in the myometrium resulted in fibrotic structure formation, altered gene expression, and disrupted signaling pathways, mirroring human UL. The loss of PRICKLE1 in the endometrial epithelium caused altered cell division, incomplete cytokinesis, and implantation defects."],"dc:identifier.other":["http://dissertations.umi.com/ku:19841"],"dc:identifier.uri":["https://hdl.handle.net/1808/38371"],"dc:language.iso":["en"],"dc:publisher":["University of Kansas"],"dc:subject":["Physiology","Endometrial Epithelium","Fibroids","Prickle1","Reproduction","Uterine Leiomyoma","Wnt/Planar Cell Polarity"],"dc:title":["The Role of PRICKLE1 in the Regulation of Uterine Structure and Physiology"],"dc:type":["Dissertation"]},"updated_at":"2026-07-24T02:46:29Z"}