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Fop-ACVR1 signals by multiple modalities in the developing zebrafish / Robyn S. Allen.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Allen, Robyn S., author.
- Language:
- English
- Subjects (All):
- Developmental biology.
- Microbiology.
- Cellular biology.
- Biology.
- Biochemistry.
- Cell and molecular biology--Penn dissertations.
- Penn dissertations--Cell and molecular biology.
- Local Subjects:
- Developmental biology.
- Microbiology.
- Cellular biology.
- Biology.
- Biochemistry.
- Cell and molecular biology--Penn dissertations.
- Penn dissertations--Cell and molecular biology.
- Genre:
- Academic theses.
- Physical Description:
- 1 online resource (154 pages)
- Contained In:
- Dissertations Abstracts International 81-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania ; Ann Arbor : ProQuest Dissertations & Theses, 2019.
- Language Note:
- English
- System Details:
- Mode of access: World Wide Web.
- text file
- Summary:
- 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.
- Notes:
- Source: Dissertations Abstracts International, Volume: 81-08, Section: B.
- Advisors: Mullins, Mary C.; Shore, Eileen M.; Committee members: Olena Jacenko; Susan Volk; Maurizio Pacifici; Michael Pack.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2019.
- Local Notes:
- School code: 0175
- ISBN:
- 9781392480106
- Access Restriction:
- Restricted for use by site license.
- This item is not available from ProQuest Dissertations & Theses.
- This item must not be sold to any third party vendors.
- This item must not be added to any third party search indexes.
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