{"id":{"repo_id":"toronto-retro","oai_identifier":"oai:utoronto.scholaris.ca:1807/139069"},"canonical_url":"https://search.dev.ndltd.org/etd/toronto-retro/oai:utoronto.scholaris.ca:1807/139069","repository":{"repo_id":"toronto-retro","name":"University of Toronto","base_url":"https://utoronto.scholaris.ca/server/oai/request"},"display":{"title":"Investigating the Biological Mechanisms Underlying Axis Morphogenesis Using a Novel Zebrafish Model of Idiopathic-like Scoliosis","abstract":"Scoliosis is characterized by an abnormal lateral curvature and three-dimensional rotation of the spine and adolescent idiopathic scoliosis (AIS), which has no known cause, affects about 4% of children worldwide. As a result of the complex genetic landscape of AIS as well as the historical lack of appropriate animal models, treatment options for AIS patients are limited to bracing and surgery. The Ciruna Lab generated the first genetically defined developmental model of idiopathic-like scoliosis (ptk7a mutant zebrafish) and has characterized a number of zebrafish IS mutants. Although our lab has previously implicated motile cilia dysfunction, cerebrospinal fluid (CSF) flow defects and neuroinflammation in zebrafish models of AIS, loss of cilia motility in humans does not fully associate with scoliosis, suggesting other pathogenic mechanisms remain to be determined. To address this gap, I characterized a novel zebrafish mutant, dmh4/+, that presents with idiopathic-like scoliosis during juvenile stages in the absence of motile cilia defects. Importantly, dmh4/dmh4 mutants present with a curly tail down (CTD) phenotype and are embryonic lethal. Using functional genetic approaches, I demonstrated that a dominant mutation in the gene scospondin (sspo) causes both the dmh4 scoliosis and CTD phenotypes. I showed that both CTD and scoliotic zebrafish mutants have abnormal accumulations of Sspo in the CNS and defects in Reissner’s fiber (RF), a proteinaceous aggregation of Sspo that runs down the central canal of the spine, suggesting Sspo is required for proper spine morphogenesis. Downstream of Sspo and RF defects, neuroinflammation is associated with axial curvatures in sspodmh4/+ and sspodmh4/dmh4 mutants. Therefore, we propose that Sspo defects and neuroinflammation are conserved mechanisms driving spinal curvatures in zebrafish IS models and that sspodmh4/dmh4 CTD is an embryonic surrogate phenotype for scoliosis. Furthermore, I demonstrated that Sspo and RF are not sufficient for proper axial morphogenesis, implicated dysregulation of the ECM and notochord morphogenesis in CTD pathogenesis and showed that overexpression of ECM genes in the notochord can modulate the zebrafish embryonic axis. Overall, my work furthers our understanding of the biological mechanisms perturbed in AIS and may one day aid in the diagnosis and treatment of human AIS patients.","abstract_html":"Scoliosis is characterized by an abnormal lateral curvature and three-dimensional rotation of the spine and adolescent idiopathic scoliosis (AIS), which has no known cause, affects about 4% of children worldwide. As a result of the complex genetic landscape of AIS as well as the historical lack of appropriate animal models, treatment options for AIS patients are limited to bracing and surgery. The Ciruna Lab generated the first genetically defined developmental model of idiopathic-like scoliosis (ptk7a mutant zebrafish) and has characterized a number of zebrafish IS mutants. Although our lab has previously implicated motile cilia dysfunction, cerebrospinal fluid (CSF) flow defects and neuroinflammation in zebrafish models of AIS, loss of cilia motility in humans does not fully associate with scoliosis, suggesting other pathogenic mechanisms remain to be determined. To address this gap, I characterized a novel zebrafish mutant, dmh4/+, that presents with idiopathic-like scoliosis during juvenile stages in the absence of motile cilia defects. Importantly, dmh4/dmh4 mutants present with a curly tail down (CTD) phenotype and are embryonic lethal. Using functional genetic approaches, I demonstrated that a dominant mutation in the gene scospondin (sspo) causes both the dmh4 scoliosis and CTD phenotypes. I showed that both CTD and scoliotic zebrafish mutants have abnormal accumulations of Sspo in the CNS and defects in Reissner’s fiber (RF), a proteinaceous aggregation of Sspo that runs down the central canal of the spine, suggesting Sspo is required for proper spine morphogenesis. Downstream of Sspo and RF defects, neuroinflammation is associated with axial curvatures in sspodmh4/+ and sspodmh4/dmh4 mutants. Therefore, we propose that Sspo defects and neuroinflammation are conserved mechanisms driving spinal curvatures in zebrafish IS models and that sspodmh4/dmh4 CTD is an embryonic surrogate phenotype for scoliosis. Furthermore, I demonstrated that Sspo and RF are not sufficient for proper axial morphogenesis, implicated dysregulation of the ECM and notochord morphogenesis in CTD pathogenesis and showed that overexpression of ECM genes in the notochord can modulate the zebrafish embryonic axis. Overall, my work furthers our understanding of the biological mechanisms perturbed in AIS and may one day aid in the diagnosis and treatment of human AIS patients.","abstract_has_math":false,"creators":["Rose, Chloe Danielle"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Molecular Genetics","school":null,"contributors":[],"advisors":["Ciruna, Brian"],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-11","date_published":"2022-11","updated_at":"2026-07-27T21:28:02Z","subjects":[],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1807/139069","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Ciruna, Brian"]},{"key":"dc:contributor.department","label":"Department","values":["Molecular Genetics"]},{"key":"dc:creator","label":"Author","values":["Rose, Chloe Danielle"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2022-11"]},{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2024-06-28T04:12:38Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2024-06-28T04:12:38Z"]},{"key":"dc:date.issued","label":"Date","values":["2022-11"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/1807/139069"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Scoliosis is characterized by an abnormal lateral curvature and three-dimensional rotation of the spine and adolescent idiopathic scoliosis (AIS), which has no known cause, affects about 4% of children worldwide. As a result of the complex genetic landscape of AIS as well as the historical lack of appropriate animal models, treatment options for AIS patients are limited to bracing and surgery. The Ciruna Lab generated the first genetically defined developmental model of idiopathic-like scoliosis (ptk7a mutant zebrafish) and has characterized a number of zebrafish IS mutants. Although our lab has previously implicated motile cilia dysfunction, cerebrospinal fluid (CSF) flow defects and neuroinflammation in zebrafish models of AIS, loss of cilia motility in humans does not fully associate with scoliosis, suggesting other pathogenic mechanisms remain to be determined. To address this gap, I characterized a novel zebrafish mutant, dmh4/+, that presents with idiopathic-like scoliosis during juvenile stages in the absence of motile cilia defects. Importantly, dmh4/dmh4 mutants present with a curly tail down (CTD) phenotype and are embryonic lethal. Using functional genetic approaches, I demonstrated that a dominant mutation in the gene scospondin (sspo) causes both the dmh4 scoliosis and CTD phenotypes. I showed that both CTD and scoliotic zebrafish mutants have abnormal accumulations of Sspo in the CNS and defects in Reissner’s fiber (RF), a proteinaceous aggregation of Sspo that runs down the central canal of the spine, suggesting Sspo is required for proper spine morphogenesis. Downstream of Sspo and RF defects, neuroinflammation is associated with axial curvatures in sspodmh4/+ and sspodmh4/dmh4 mutants. Therefore, we propose that Sspo defects and neuroinflammation are conserved mechanisms driving spinal curvatures in zebrafish IS models and that sspodmh4/dmh4 CTD is an embryonic surrogate phenotype for scoliosis. Furthermore, I demonstrated that Sspo and RF are not sufficient for proper axial morphogenesis, implicated dysregulation of the ECM and notochord morphogenesis in CTD pathogenesis and showed that overexpression of ECM genes in the notochord can modulate the zebrafish embryonic axis. Overall, my work furthers our understanding of the biological mechanisms perturbed in AIS and may one day aid in the diagnosis and treatment of human AIS patients."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph.D."]},{"key":"dc:title","label":"Title","values":["Investigating the Biological Mechanisms Underlying Axis Morphogenesis Using a Novel Zebrafish Model of Idiopathic-like Scoliosis"]}]}],"canonical_facts":{"dc:contributor.advisor":["Ciruna, Brian"],"dc:contributor.department":["Molecular Genetics"],"dc:creator":["Rose, Chloe Danielle"],"dc:date":["2022-11"],"dc:date.accessioned":["2024-06-28T04:12:38Z"],"dc:date.available":["2024-06-28T04:12:38Z"],"dc:date.issued":["2022-11"],"dc:description.abstract":["Scoliosis is characterized by an abnormal lateral curvature and three-dimensional rotation of the spine and adolescent idiopathic scoliosis (AIS), which has no known cause, affects about 4% of children worldwide. As a result of the complex genetic landscape of AIS as well as the historical lack of appropriate animal models, treatment options for AIS patients are limited to bracing and surgery. The Ciruna Lab generated the first genetically defined developmental model of idiopathic-like scoliosis (ptk7a mutant zebrafish) and has characterized a number of zebrafish IS mutants. Although our lab has previously implicated motile cilia dysfunction, cerebrospinal fluid (CSF) flow defects and neuroinflammation in zebrafish models of AIS, loss of cilia motility in humans does not fully associate with scoliosis, suggesting other pathogenic mechanisms remain to be determined. To address this gap, I characterized a novel zebrafish mutant, dmh4/+, that presents with idiopathic-like scoliosis during juvenile stages in the absence of motile cilia defects. Importantly, dmh4/dmh4 mutants present with a curly tail down (CTD) phenotype and are embryonic lethal. Using functional genetic approaches, I demonstrated that a dominant mutation in the gene scospondin (sspo) causes both the dmh4 scoliosis and CTD phenotypes. I showed that both CTD and scoliotic zebrafish mutants have abnormal accumulations of Sspo in the CNS and defects in Reissner’s fiber (RF), a proteinaceous aggregation of Sspo that runs down the central canal of the spine, suggesting Sspo is required for proper spine morphogenesis. Downstream of Sspo and RF defects, neuroinflammation is associated with axial curvatures in sspodmh4/+ and sspodmh4/dmh4 mutants. Therefore, we propose that Sspo defects and neuroinflammation are conserved mechanisms driving spinal curvatures in zebrafish IS models and that sspodmh4/dmh4 CTD is an embryonic surrogate phenotype for scoliosis. Furthermore, I demonstrated that Sspo and RF are not sufficient for proper axial morphogenesis, implicated dysregulation of the ECM and notochord morphogenesis in CTD pathogenesis and showed that overexpression of ECM genes in the notochord can modulate the zebrafish embryonic axis. Overall, my work furthers our understanding of the biological mechanisms perturbed in AIS and may one day aid in the diagnosis and treatment of human AIS patients."],"dc:description.degree":["Ph.D."],"dc:identifier.uri":["http://hdl.handle.net/1807/139069"],"dc:title":["Investigating the Biological Mechanisms Underlying Axis Morphogenesis Using a Novel Zebrafish Model of Idiopathic-like Scoliosis"],"dc:type":["Thesis"]},"updated_at":"2026-07-27T21:28:02Z"}