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Identification of Semaphorin Receptors as Novel Regulators of Wnt and Hedgehog Signaling
Identification of Semaphorin Receptors as Novel Regulators of Wnt and Hedgehog Signaling
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211153008
- ISBN
- 9798384044574
- DDC
- 574
- 저자명
- Hoard, Tyler M.
- 서명/저자
- Identification of Semaphorin Receptors as Novel Regulators of Wnt and Hedgehog Signaling
- 발행사항
- [Sl] : University of Michigan, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 251 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-03, Section: B.
- 주기사항
- Advisor: Giger, Roman.
- 학위논문주기
- Thesis (Ph.D.)--University of Michigan, 2024.
- 초록/해제
- 요약Morphogen signaling pathways play essential roles in embryonic and postnatal development and adult tissue homeostasis. These pathways act in precisely controlled spatiotemporal patterns to properly regulate biological processes. Two of these critically important pathways are Hedgehog (HH) and Wnt signaling, key regulators of embryogenesis that, when dysregulated, can also cause birth defects and developmental disorders, or drive pediatric and adult cancers. Despite over forty years of research, we still do not have a complete understanding of the mechanisms that regulate these key developmental signals. Previous studies have identified Neuropilins (NRPs), single-pass transmembrane proteins that are well-characterized receptors of Semaphorin (SEMA) ligands, as positive regulators of HH signaling. In the context of SEMA signaling, NRPs function in a co-receptor complex with Plexins (PLXNs), which contain an intracellular bipartite GAP domain that regulates the activity of cytoplasmic GTPases. However, a potential role for PLXNs in HH signaling has not been explored. Further, potential roles for SEMA receptors in Wnt signaling have also not been explored.In this thesis, I present evidence that PLXNs utilize their intracellular GAP domain to promote HH signaling at the level of the GLI transcription factors. Strikingly, PLXN-dependent HH pathway promotion is dependent on the presence of primary cilia, despite the finding that PLXNs themselves do not localize to the primary cilium. I also provide evidence that depletion of PLXNs in NIH/3T3 fibroblasts abrogates HH pathway activity. Further, homozygous deletion of Plxna1 or Plxna2 in the postnatal mouse hippocampus results in decreased HH signaling, identifying a role for PLXNs in postnatal HH-dependent development.I also identify both PLXNs and NRPs as negative regulators of the Wnt pathway in both NIH/3T3 fibroblasts and HEK293T epithelial cells. Mechanistically, PLXN-dependent Wnt pathway antagonism requires the PLXN cytoplasmic domain. I also find that genetic deletion of both members of the NRP family results in elevated baseline Wnt signaling in NIH/3T3 fibroblast cells. Both PLXNs and NRPs antagonize Wnt signaling by destabilizing β-catenin (CTNNB1), including stabilized versions of CTNNB1 (containing mutations that prevent phosphorylation at residues that normally target CTNNB1 for proteasomal degradation). Notably, NRPs drive CTNNB1 degradation in a GSK3β/CK1-dependent manner, while PLXNs promote CTNNB1 degradation independently of these kinases. Interestingly, these results are achieved via a mechanism independent from primary cilia and Dishevelled (DVL). Together, this thesis identifies SEMA receptors as novel, multifunctional regulators of both the HH and Wnt signaling pathways.
- 일반주제명
- Cellular biology
- 일반주제명
- Molecular biology
- 일반주제명
- Developmental biology
- 키워드
- Hedgehog
- 키워드
- Semaphorin
- 키워드
- Plexin
- 키워드
- Neuropilin
- 키워드
- Hippocampus
- 기타저자
- University of Michigan Cell and Developmental Biology
- 기본자료저록
- Dissertations Abstracts International. 86-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520250211153008
■006m o d
■007cr#unu||||||||
■020 ▼a9798384044574
■035 ▼a(MiAaPQ)AAI31631431
■035 ▼a(MiAaPQ)umichrackham005836
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aHoard, Tyler M.
■24510▼aIdentification of Semaphorin Receptors as Novel Regulators of Wnt and Hedgehog Signaling
■260 ▼a[Sl]▼bUniversity of Michigan▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a251 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-03, Section: B.
■500 ▼aAdvisor: Giger, Roman.
■5021 ▼aThesis (Ph.D.)--University of Michigan, 2024.
■520 ▼aMorphogen signaling pathways play essential roles in embryonic and postnatal development and adult tissue homeostasis. These pathways act in precisely controlled spatiotemporal patterns to properly regulate biological processes. Two of these critically important pathways are Hedgehog (HH) and Wnt signaling, key regulators of embryogenesis that, when dysregulated, can also cause birth defects and developmental disorders, or drive pediatric and adult cancers. Despite over forty years of research, we still do not have a complete understanding of the mechanisms that regulate these key developmental signals. Previous studies have identified Neuropilins (NRPs), single-pass transmembrane proteins that are well-characterized receptors of Semaphorin (SEMA) ligands, as positive regulators of HH signaling. In the context of SEMA signaling, NRPs function in a co-receptor complex with Plexins (PLXNs), which contain an intracellular bipartite GAP domain that regulates the activity of cytoplasmic GTPases. However, a potential role for PLXNs in HH signaling has not been explored. Further, potential roles for SEMA receptors in Wnt signaling have also not been explored.In this thesis, I present evidence that PLXNs utilize their intracellular GAP domain to promote HH signaling at the level of the GLI transcription factors. Strikingly, PLXN-dependent HH pathway promotion is dependent on the presence of primary cilia, despite the finding that PLXNs themselves do not localize to the primary cilium. I also provide evidence that depletion of PLXNs in NIH/3T3 fibroblasts abrogates HH pathway activity. Further, homozygous deletion of Plxna1 or Plxna2 in the postnatal mouse hippocampus results in decreased HH signaling, identifying a role for PLXNs in postnatal HH-dependent development.I also identify both PLXNs and NRPs as negative regulators of the Wnt pathway in both NIH/3T3 fibroblasts and HEK293T epithelial cells. Mechanistically, PLXN-dependent Wnt pathway antagonism requires the PLXN cytoplasmic domain. I also find that genetic deletion of both members of the NRP family results in elevated baseline Wnt signaling in NIH/3T3 fibroblast cells. Both PLXNs and NRPs antagonize Wnt signaling by destabilizing β-catenin (CTNNB1), including stabilized versions of CTNNB1 (containing mutations that prevent phosphorylation at residues that normally target CTNNB1 for proteasomal degradation). Notably, NRPs drive CTNNB1 degradation in a GSK3β/CK1-dependent manner, while PLXNs promote CTNNB1 degradation independently of these kinases. Interestingly, these results are achieved via a mechanism independent from primary cilia and Dishevelled (DVL). Together, this thesis identifies SEMA receptors as novel, multifunctional regulators of both the HH and Wnt signaling pathways.
■590 ▼aSchool code: 0127.
■650 4▼aCellular biology
■650 4▼aMolecular biology
■650 4▼aDevelopmental biology
■653 ▼aHedgehog
■653 ▼aSemaphorin
■653 ▼aPlexin
■653 ▼aNeuropilin
■653 ▼aHippocampus
■653 ▼aDevelopmental disorders
■690 ▼a0307
■690 ▼a0758
■690 ▼a0379
■71020▼aUniversity of Michigan▼bCell and Developmental Biology.
■7730 ▼tDissertations Abstracts International▼g86-03B.
■790 ▼a0127
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17164491▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
