부산대학교 도서관

Non-syndromic mitral valve prolapse (MVP) is the most common heart valve disease affecting 2.4% of the population. Recent studies have identified genetic defects in primary cilia as causative to MVP, although the mechanism of their action is currently unknown. Using a series of gene inactivation approaches, we define a paracrine mechanism by which endocardially-expressed Desert Hedgehog (DHH) activates primary cilia signaling on neighboring valve interstitial cells. High-resolution imaging and functional assays show that DHH de-represses smoothened at the primary cilia, resulting in kinase activation of RAC1 through the RAC1-GEF, TIAM1. Activation of this non-canonical hedgehog pathway stimulates α-smooth actin organization and ECM remodeling. Genetic or pharmacological perturbation of this pathway results in enlarged valves that progress to a myxomatous phenotype, similar to valves seen in MVP patients. These data identify a potential molecular origin for MVP as well as establish a paracrine DHH-primary cilium cross-talk mechanism that is likely applicable across developmental tissue types. • Endocardial DHH activates primary cilium on valve interstitial cells through a paracrine cross-talk mechanism. • Non-Canonical hedgehog signaling functions through the primary cilium during valve development. • Desert Hedgehog activates TIAM1-RAC1 kinase activity through the primary cilium. • Alpha-Smooth Muscle Actin is activated through a DHH-TIAM1-RAC1 signaling event to stimulate cell and tissue remodeling. • Altered DHH-cilia signaling impairs cytoskeleton remodeling during development and can cause MVP later in life. [ABSTRACT FROM AUTHOR]