1. Desert hedgehog-primary cilia cross talk shapes mitral valve tissue by organizing smooth muscle actin.
- Author
-
Fulmer D, Toomer KA, Glover J, Guo L, Moore K, Moore R, Stairley R, Gensemer C, Abrol S, Rumph MK, Emetu F, Lipschutz JH, McDowell C, Bian J, Wang C, Beck T, Wessels A, Renault MA, and Norris RA
- Subjects
- Actins metabolism, Animals, Extracellular Matrix metabolism, Heart Valve Diseases, Hedgehog Proteins physiology, Mice, Mitral Valve Prolapse genetics, Mitral Valve Prolapse metabolism, Muscle, Smooth metabolism, Muscle, Smooth physiology, Myocytes, Smooth Muscle metabolism, Neuropeptides metabolism, Phenotype, Signal Transduction, Transcription Factors metabolism, rac1 GTP-Binding Protein metabolism, Cilia metabolism, Hedgehog Proteins metabolism, Mitral Valve embryology
- Abstract
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., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF