{"id":{"repo_id":"penn","oai_identifier":"oai:repository.upenn.edu:20.500.14332/30601"},"canonical_url":"https://search.dev.ndltd.org/etd/penn/oai:repository.upenn.edu:20.500.14332/30601","repository":{"repo_id":"penn","name":"University of Pennsylvania","base_url":"https://repository.upenn.edu/server/oai/request"},"display":{"title":"Fop-Acvr1 Signals By Multiple Modalities In The Developing Zebrafish","abstract":"Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disorder characterized by skeletal malformations and progressive extraskeletal ossification. All cases of FOP are caused by activating mutations in the GS or kinase domains of the type I BMP/TGFβ cell surface receptor, ACVR1, which over-activate signaling through phospho-Smad1/5 (pSmad1/5). To investigate the uncertain mechanism by which FOP-ACVR1 enhances pSmad1/5 activation, we used a zebrafish embryonic dorsoventral (DV) patterning assay for BMP signaling. In this system, misexpression of human ACVR1-R206H causes increased pSmad1/5 signaling and ventralization of zebrafish embryos. To pattern the zebrafish DV axis, Acvr1l, the zebrafish homologue of human ACVR1, signals in response to BMP ligand within a heterotetrameric, type I and II receptor complex. Previous studies have demonstrated that type II BMP receptors are required for the activity of FOP-ACVR1, however the roles of ligand and other type I BMP receptors are less well understood. We determined that the FOP mutants ACVR1-R206H and -G328R do not require their ligand binding domain to over-activate BMP signaling in DV patterning. However, intact ACVR1-R206H and G328R have the ability to respond to BMP ligand. Additionally, BMPR1, a type I BMP receptor which is normally required for BMP-mediated patterning of the embryo, is dispensable for both ligand-independent and ligand-responsive BMP signaling activation by ACVR1-R206H. Both ACVR1-R206H and -G328R require a GS domain, and presumptive type II BMP receptor activity. However, ACVR1-R206H and -G328R have a reduced requirement for serine and threonine residues within the GS domain compared to ACVR1. Interestingly, these FOP mutants, differ from each other in their GS domain residue requirements for ligand-independent signaling. Over-active signaling by ACVR1-R206H and -G328R can be abrogated by competitive ATP inhibition, confirming that kinase activity is required for over-active signaling. Lastly, Acvr1l-R203H, the zebrafish homolog of ACVR1-R206H, does not have over-active signaling. However, the human ACVR1 kinase domain is sufficient to facilitate over-active signaling by Acvr1l-R203H. These data provide new insight into how the ligand-receptor complex assembles and is regulated in both wild-type and FOP BMP pathway signaling and elucidate potential targets for the treatment of FOP.","abstract_html":"Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disorder characterized by skeletal malformations and progressive extraskeletal ossification. All cases of FOP are caused by activating mutations in the GS or kinase domains of the type I BMP/TGFβ cell surface receptor, ACVR1, which over-activate signaling through phospho-Smad1/5 (pSmad1/5). To investigate the uncertain mechanism by which FOP-ACVR1 enhances pSmad1/5 activation, we used a zebrafish embryonic dorsoventral (DV) patterning assay for BMP signaling. In this system, misexpression of human ACVR1-R206H causes increased pSmad1/5 signaling and ventralization of zebrafish embryos. To pattern the zebrafish DV axis, Acvr1l, the zebrafish homologue of human ACVR1, signals in response to BMP ligand within a heterotetrameric, type I and II receptor complex. Previous studies have demonstrated that type II BMP receptors are required for the activity of FOP-ACVR1, however the roles of ligand and other type I BMP receptors are less well understood. We determined that the FOP mutants ACVR1-R206H and -G328R do not require their ligand binding domain to over-activate BMP signaling in DV patterning. However, intact ACVR1-R206H and G328R have the ability to respond to BMP ligand. Additionally, BMPR1, a type I BMP receptor which is normally required for BMP-mediated patterning of the embryo, is dispensable for both ligand-independent and ligand-responsive BMP signaling activation by ACVR1-R206H. Both ACVR1-R206H and -G328R require a GS domain, and presumptive type II BMP receptor activity. However, ACVR1-R206H and -G328R have a reduced requirement for serine and threonine residues within the GS domain compared to ACVR1. Interestingly, these FOP mutants, differ from each other in their GS domain residue requirements for ligand-independent signaling. Over-active signaling by ACVR1-R206H and -G328R can be abrogated by competitive ATP inhibition, confirming that kinase activity is required for over-active signaling. Lastly, Acvr1l-R203H, the zebrafish homolog of ACVR1-R206H, does not have over-active signaling. However, the human ACVR1 kinase domain is sufficient to facilitate over-active signaling by Acvr1l-R203H. These data provide new insight into how the ligand-receptor complex assembles and is regulated in both wild-type and FOP BMP pathway signaling and elucidate potential targets for the treatment of FOP.","abstract_has_math":false,"creators":["Allen, Robyn S"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Mary C. Mullins","Eileen M. Shore"],"committee_chairs":[],"committee_members":[],"year":2019,"date_issued":"2019","date_published":"2019","updated_at":"2026-07-24T03:47:28Z","subjects":[],"languages":["en"],"rights":["Robyn S Allen"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://repository.upenn.edu/handle/20.500.14332/30601","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Mary C. Mullins","Eileen M. Shore"]},{"key":"dc:creator","label":"Author","values":["Allen, Robyn S"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2023-05-17T23:20:56.000"]},{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2023-05-22T17:45:29Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2021-01-01T00:00:00Z"]},{"key":"dc:date.issued","label":"Date","values":["2019"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation/Thesis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["Robyn S Allen"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://repository.upenn.edu/handle/20.500.14332/30601"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disorder characterized by skeletal malformations and progressive extraskeletal ossification. All cases of FOP are caused by activating mutations in the GS or kinase domains of the type I BMP/TGFβ cell surface receptor, ACVR1, which over-activate signaling through phospho-Smad1/5 (pSmad1/5). To investigate the uncertain mechanism by which FOP-ACVR1 enhances pSmad1/5 activation, we used a zebrafish embryonic dorsoventral (DV) patterning assay for BMP signaling. In this system, misexpression of human ACVR1-R206H causes increased pSmad1/5 signaling and ventralization of zebrafish embryos. To pattern the zebrafish DV axis, Acvr1l, the zebrafish homologue of human ACVR1, signals in response to BMP ligand within a heterotetrameric, type I and II receptor complex. Previous studies have demonstrated that type II BMP receptors are required for the activity of FOP-ACVR1, however the roles of ligand and other type I BMP receptors are less well understood. We determined that the FOP mutants ACVR1-R206H and -G328R do not require their ligand binding domain to over-activate BMP signaling in DV patterning. However, intact ACVR1-R206H and G328R have the ability to respond to BMP ligand. Additionally, BMPR1, a type I BMP receptor which is normally required for BMP-mediated patterning of the embryo, is dispensable for both ligand-independent and ligand-responsive BMP signaling activation by ACVR1-R206H. Both ACVR1-R206H and -G328R require a GS domain, and presumptive type II BMP receptor activity. However, ACVR1-R206H and -G328R have a reduced requirement for serine and threonine residues within the GS domain compared to ACVR1. Interestingly, these FOP mutants, differ from each other in their GS domain residue requirements for ligand-independent signaling. Over-active signaling by ACVR1-R206H and -G328R can be abrogated by competitive ATP inhibition, confirming that kinase activity is required for over-active signaling. Lastly, Acvr1l-R203H, the zebrafish homolog of ACVR1-R206H, does not have over-active signaling. However, the human ACVR1 kinase domain is sufficient to facilitate over-active signaling by Acvr1l-R203H. These data provide new insight into how the ligand-receptor complex assembles and is regulated in both wild-type and FOP BMP pathway signaling and elucidate potential targets for the treatment of FOP."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Doctor of Philosophy (PhD)"]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Fop-Acvr1 Signals By Multiple Modalities In The Developing Zebrafish"]}]}],"canonical_facts":{"dc:contributor.advisor":["Mary C. Mullins","Eileen M. Shore"],"dc:creator":["Allen, Robyn S"],"dc:date":["2023-05-17T23:20:56.000"],"dc:date.accessioned":["2023-05-22T17:45:29Z"],"dc:date.available":["2021-01-01T00:00:00Z"],"dc:date.issued":["2019"],"dc:description.abstract":["Fibrodysplasia ossificans progressiva (FOP) is a rare human genetic disorder characterized by skeletal malformations and progressive extraskeletal ossification. All cases of FOP are caused by activating mutations in the GS or kinase domains of the type I BMP/TGFβ cell surface receptor, ACVR1, which over-activate signaling through phospho-Smad1/5 (pSmad1/5). To investigate the uncertain mechanism by which FOP-ACVR1 enhances pSmad1/5 activation, we used a zebrafish embryonic dorsoventral (DV) patterning assay for BMP signaling. In this system, misexpression of human ACVR1-R206H causes increased pSmad1/5 signaling and ventralization of zebrafish embryos. To pattern the zebrafish DV axis, Acvr1l, the zebrafish homologue of human ACVR1, signals in response to BMP ligand within a heterotetrameric, type I and II receptor complex. Previous studies have demonstrated that type II BMP receptors are required for the activity of FOP-ACVR1, however the roles of ligand and other type I BMP receptors are less well understood. We determined that the FOP mutants ACVR1-R206H and -G328R do not require their ligand binding domain to over-activate BMP signaling in DV patterning. However, intact ACVR1-R206H and G328R have the ability to respond to BMP ligand. Additionally, BMPR1, a type I BMP receptor which is normally required for BMP-mediated patterning of the embryo, is dispensable for both ligand-independent and ligand-responsive BMP signaling activation by ACVR1-R206H. Both ACVR1-R206H and -G328R require a GS domain, and presumptive type II BMP receptor activity. However, ACVR1-R206H and -G328R have a reduced requirement for serine and threonine residues within the GS domain compared to ACVR1. Interestingly, these FOP mutants, differ from each other in their GS domain residue requirements for ligand-independent signaling. Over-active signaling by ACVR1-R206H and -G328R can be abrogated by competitive ATP inhibition, confirming that kinase activity is required for over-active signaling. Lastly, Acvr1l-R203H, the zebrafish homolog of ACVR1-R206H, does not have over-active signaling. However, the human ACVR1 kinase domain is sufficient to facilitate over-active signaling by Acvr1l-R203H. These data provide new insight into how the ligand-receptor complex assembles and is regulated in both wild-type and FOP BMP pathway signaling and elucidate potential targets for the treatment of FOP."],"dc:description.degree":["Doctor of Philosophy (PhD)"],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://repository.upenn.edu/handle/20.500.14332/30601"],"dc:language":["en"],"dc:rights":["Robyn S Allen"],"dc:title":["Fop-Acvr1 Signals By Multiple Modalities In The Developing Zebrafish"],"dc:type":["Dissertation/Thesis"]},"updated_at":"2026-07-24T03:47:28Z"}