Back to Search
Start Over
Desert hedgehog-primary cilia cross talk shapes mitral valve tissue by organizing smooth muscle actin.
- Source :
-
Developmental biology [Dev Biol] 2020 Jul 01; Vol. 463 (1), pp. 26-38. Date of Electronic Publication: 2020 Mar 06. - Publication Year :
- 2020
-
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.<br />Competing Interests: Declaration of competing interest None.<br /> (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1095-564X
- Volume :
- 463
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Developmental biology
- Publication Type :
- Academic Journal
- Accession number :
- 32151560
- Full Text :
- https://doi.org/10.1016/j.ydbio.2020.03.003