서브메뉴
검색
Mechanical and Transcriptional Roles for Primary Cilia During Intracardiac Cushion EndoMT
Mechanical and Transcriptional Roles for Primary Cilia During Intracardiac Cushion EndoMT
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20250211151023
- ISBN
- 9798383372296
- DDC
- 574
- 서명/저자
- Mechanical and Transcriptional Roles for Primary Cilia During Intracardiac Cushion EndoMT
- 발행사항
- [Sl] : Yale University, 2024
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- 형태사항
- 184 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-01, Section: B.
- 주기사항
- Advisor: Brueckner, Martina.
- 학위논문주기
- Thesis (Ph.D.)--Yale University, 2024.
- 초록/해제
- 요약The first organ to develop in vertebrates is the heart, a necessary process for all other organ systems that follow. Proper development of the embryonic heart relies on the ability for intracardiac cells to sense and translate complex mechanical forces into transcriptional signals. Failure to do so results in numerous cardiac abnormalities, such as thinned compact myocardium, stunted trabeculations and atrioventricular canal defects. These structural abnormalities are a common occurrence in congenital heart disease (CHD), which affects more than 1% of all live births. Nonetheless, the mechanism by which mechanical forces are generated, sensed, and integrated into cardiac development remains poorly understood. This body of work describes a method by which blood flow is converted into spatial regulation of endocardial cushion formation through a known mechanosensor, the primary cilium.Though many forces exist in the developing heart, blood flow-derived wall shear stress (WSS) is the most critical for heart valve formation. Here, we uncover a WSS-specific mechanosensor, the primary cilium, on endocardial cells lining the heart lumen in regions of valve development in both mouse and zebrafish embryos. We identify a role for these primary cilia in the spatial regulation of cushion formation, the first stage of valve development, by regionally restricting endothelial to mesenchymal transition (EndoMT) via modulation of Kruppel-like Factor 4 (Klf4) in mouse. KLF4 is a mechanosensitive transcription factor that we find negatively correlates with EndoMT progression. Our results indicate that endocardial cells that experience high WSS lose their cilia, correlating with KLF4 downregulation and permissive EndoMT only in high WSS regions. Mouse embryos constitutively lacking cilia (cilia KOs) paradoxically exhibit a blood-flow dependent increase in KLF4 expression, independent of upstream left-right abnormalities. These results suggest that initial cilia presence and subsequent loss on endocardium in response to cardiac function is needed for downregulation of KLF4. Overabundance of KLF4 in cilia KOs results in significantly impaired EndoMT progression and cushion cellularization. Single-Nuc RNAseq on isolated e9.5 wild-type and cilia KO hearts revealed that hearts lacking cilia fail to progress from mid- to late-EndoMT, a pseudo-stage that corresponds with Klf4 downregulation in wild-type hearts. Cilia KO hearts retain endothelial markers during EndoMT and fail to express mesenchymal and EndoMT genes that are negatively regulated by KLF4. Finally, Gene Ontology terms for mesenchymal and valve development are downregulated in cilia KO hearts, while terms for vascular identity/integrity are upregulated. Taken together, these data identify a novel mechanosensory role for EC primary cilia in regulating EndoMT localization and progression via KLF4 expression during cushion development.
- 일반주제명
- Developmental biology
- 일반주제명
- Physiology
- 일반주제명
- Nutrition
- 키워드
- Cilia
- 키워드
- Endocardium
- 키워드
- Mechanosensation
- 기타저자
- Yale University Genetics
- 기본자료저록
- Dissertations Abstracts International. 86-01B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
008250123s2024 us c eng d■001000017160457
■00520250211151023
■006m o d
■007cr#unu||||||||
■020 ▼a9798383372296
■035 ▼a(MiAaPQ)AAI30996637
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aBerg, Kathryn Soule.
■24510▼aMechanical and Transcriptional Roles for Primary Cilia During Intracardiac Cushion EndoMT
■260 ▼a[Sl]▼bYale University▼c2024
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2024
■300 ▼a184 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-01, Section: B.
■500 ▼aAdvisor: Brueckner, Martina.
■5021 ▼aThesis (Ph.D.)--Yale University, 2024.
■520 ▼aThe first organ to develop in vertebrates is the heart, a necessary process for all other organ systems that follow. Proper development of the embryonic heart relies on the ability for intracardiac cells to sense and translate complex mechanical forces into transcriptional signals. Failure to do so results in numerous cardiac abnormalities, such as thinned compact myocardium, stunted trabeculations and atrioventricular canal defects. These structural abnormalities are a common occurrence in congenital heart disease (CHD), which affects more than 1% of all live births. Nonetheless, the mechanism by which mechanical forces are generated, sensed, and integrated into cardiac development remains poorly understood. This body of work describes a method by which blood flow is converted into spatial regulation of endocardial cushion formation through a known mechanosensor, the primary cilium.Though many forces exist in the developing heart, blood flow-derived wall shear stress (WSS) is the most critical for heart valve formation. Here, we uncover a WSS-specific mechanosensor, the primary cilium, on endocardial cells lining the heart lumen in regions of valve development in both mouse and zebrafish embryos. We identify a role for these primary cilia in the spatial regulation of cushion formation, the first stage of valve development, by regionally restricting endothelial to mesenchymal transition (EndoMT) via modulation of Kruppel-like Factor 4 (Klf4) in mouse. KLF4 is a mechanosensitive transcription factor that we find negatively correlates with EndoMT progression. Our results indicate that endocardial cells that experience high WSS lose their cilia, correlating with KLF4 downregulation and permissive EndoMT only in high WSS regions. Mouse embryos constitutively lacking cilia (cilia KOs) paradoxically exhibit a blood-flow dependent increase in KLF4 expression, independent of upstream left-right abnormalities. These results suggest that initial cilia presence and subsequent loss on endocardium in response to cardiac function is needed for downregulation of KLF4. Overabundance of KLF4 in cilia KOs results in significantly impaired EndoMT progression and cushion cellularization. Single-Nuc RNAseq on isolated e9.5 wild-type and cilia KO hearts revealed that hearts lacking cilia fail to progress from mid- to late-EndoMT, a pseudo-stage that corresponds with Klf4 downregulation in wild-type hearts. Cilia KO hearts retain endothelial markers during EndoMT and fail to express mesenchymal and EndoMT genes that are negatively regulated by KLF4. Finally, Gene Ontology terms for mesenchymal and valve development are downregulated in cilia KO hearts, while terms for vascular identity/integrity are upregulated. Taken together, these data identify a novel mechanosensory role for EC primary cilia in regulating EndoMT localization and progression via KLF4 expression during cushion development.
■590 ▼aSchool code: 0265.
■650 4▼aDevelopmental biology
■650 4▼aPhysiology
■650 4▼aNutrition
■653 ▼aCilia
■653 ▼aEndocardial cushions
■653 ▼aEndocardium
■653 ▼aMechanosensation
■653 ▼aCongenital heart disease
■690 ▼a0758
■690 ▼a0570
■690 ▼a0719
■71020▼aYale University▼bGenetics.
■7730 ▼tDissertations Abstracts International▼g86-01B.
■790 ▼a0265
■791 ▼aPh.D.
■792 ▼a2024
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17160457▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
