Fig. 6 |. Spatiotemporal distribution of primary cilia during valve development.

The initial critical steps of cushion formation and remodelling in three vertebrate model organisms are presented (part a). The cellular processes are conserved across mice, chicks and zebrafish, and the figure indicates the spatial context of the forming valves within the heart at relevant times during development in each model. Haematoxylin and eosin (H&E)-stained sections of mouse hearts at E12.5 (part b). Left panels show hearts from wild-type (WT) mice, middle panels from mice with mutant Lrd (encoding left–right dynein), which have left–right patterning defects, and right panels from mice with deletion of Kif3a (encoding a motor subunit of the heterotrimeric kinesin complex). The arrows pinpoint the lack of cushion cellularization in cilia mutants irrespective of left–right patterning defects. Histopathological images of mouse hearts with deletion of Cc2d2a (which encodes a basal body component) at E15.5, which have normal outflow tract cushions but atrioventricular (AV) cushions with dextrocardia (part c) and AV septal defects (AVSDs) (part d). Mutant AV cushions are improperly formed (part e). Mice with conditional deletion of Ift88 (Nfatc1^Cre;Ift88^f/f), which encodes an intraflagellar transport component, have cushion remodelling phenotypes that result in bicuspid aortic valve (BAV) defects compared with mice with WT Ift88 (Nfatc1^Cre−;Ift88^f/f) (parts f, g). This phenotype was highly penetrant, being observed in 19 of 28 mice with the genetic deletion. The left panel shows H&E-stained sections and the right panel shows 3D reconstruction images depicting the penetrance of this phenotype. A, atrium; Ao, aorta; Atr, atrium; AVC, atrioventricular canal; ECC, endocardial cushion; EndoMT, endothelial-to-mesenchymal transition; HH, Hamburger–Hamilton; hpf, hours post-fertilization; LA, left atrium; LC, left coronary; LV, left ventricle; mLV, morphological left ventricle; mRV, morphological right ventricle; NC, non-coronary; OFT, outflow tract; PA, pulmonary artery; RA, right atrium; RC, right coronary; RNC, right non-coronary; RV, right ventricle; V, ventricle. Part b reprinted with permission from REF.¹¹⁵, Wiley. Parts c–e reprinted from REF.¹⁸, Springer Nature Limited. Parts f and g reprinted with permission from REF.¹⁴¹, Wiley.