AIMS: Bicuspid aortic valve (BAV), where two valve leaflets are found instead of the usual three, affects 1-2% of the general population and is associated with significant morbidity and mortality. Despite its frequency, the majority of cases remain unexplained. This is, at least in part, because there are two types of valve leaflet primordia: endocardial cushions and intercalated valve swellings (ICVS). Moreover, multiple progenitors make distinct contributions to the formation of these primordia. Genomic studies in mouse and human have suggested a correlation between BAV and malfunctional primary cilia. However, the precise requirement for cilia during early embryonic valvulogenesis remains unknown. METHODS AND RESULTS: Here, we disrupted primary cilia by deleting the ciliary gene Ift88 in the main progenitor cells forming the aortic valve using specific Cre drivers: Wnt1-Cre for neural crest cells, Isl1-Cre for second heart field (SHF) cells, Tie2-Cre for endocardial-derived cells, and Tnnt2-Cre for direct-differentiating SHF in the ICVS. Loss of Ift88, and thus primary cilia, from neural crest cells and endocardium did not impact aortic valve formation. However, primary cilia were essential in SHF cells for aortic valve leaflet formation, with over half of Ift88f/f;Isl1-Cre mutants presenting with BAV. As the valve leaflets were forming, 50% of the Ift88f/f;Isl1-Cre mutants had two small leaflets in the position of the usual posterior leaflet, meaning that at this stage, the aortic valve was quadricuspid, which then remodelled to BAV by E15.5. Mechanistic studies demonstrated premature differentiation of SHF cells as the ICVS formed, leading to the formation of a broadened ICVS that formed two posterior leaflet precursors. This abnormality in the formation of the ICVS was associated with disruption of Notch-Jag1 signalling pathway, with Jag1f/f;Isl1-Cre mutants presenting with a similar phenotype. CONCLUSION: These data show that primary cilia, via the Notch-Jag1 signalling pathway, regulate differentiation of SHF cells in the aortic valve primordia. Additionally, we identify a mechanistic link between the developmental basis of quadricuspid and bicuspid arterial valve leaflets.

• Klíčová slova
• Aortic valve, Cilia, Ift88, bicuspid aortic valve, intercalated valve swelling, second heart field,
• MeSH
• aortální chlopeň * abnormality   metabolismus   embryologie   patologie   MeSH
• bikuspidální aortální chlopeň MeSH
• buněčná diferenciace MeSH
• cilie * metabolismus   patologie   MeSH
• crista neuralis metabolismus   MeSH
• endokardové polštáře metabolismus   embryologie   patologie   MeSH
• fenotyp MeSH
• modely nemocí na zvířatech MeSH
• myši knockoutované MeSH
• myši transgenní MeSH
• nádorové supresorové proteiny MeSH
• nemoci srdečních chlopní * metabolismus   genetika   patologie   embryologie   MeSH
• protein Wnt1 genetika   metabolismus   MeSH
• receptory Notch metabolismus   MeSH
• signální transdukce MeSH
• vývojová regulace genové exprese MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nádorové supresorové proteiny MeSH
• protein Wnt1 MeSH
• receptory Notch MeSH
• Tg737Rpw protein, mouse MeSH Prohlížeč