Desert hedgehog-primary cilia cross talk shapes mitral valve tissue by organizing smooth muscle actin
Year: 2020
Type: article
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.
Source: Developmental Biology
Authors: Diana Fulmer, Katelynn A. Toomer, Janiece Glover, Lilong Guo, Kelsey Moore, Reece Moore, Rebecca Stairley, Cortney Gensemer, Sameer Abrol, Mary Kate Rumph, Faith Emetu, Joshua H. Lipschutz, Colin McDowell, Justin Bian, Christina Wang, Tyler Beck, Andy Wessels, Marie-Ange Renault, Russell A. Norris
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,500
Awards: Molecular and cellular causes of mitral valve prolapse, G1250730630, G167217301, G1999526039, G22728256, G2851587394, G2934836127, G362742471, G3766474940, G448342564, G4656156008, Genetic and Molecular Determinants of Bicuspid and Calcific Aortic Valve Disease, G547628071, G5743453972, Bioengineering Center of Regeneration and Formation of Tissues (SC BioCRAFT), G6106915579, Primary Cilia and Mitral Valve Prolapse, Training To Improve Cardiovascular Therapies, G6781035106, Dzip1 and Mitral Valve Prolapse, G804110257, G9000004278, G9000018733, G9000031680, G9000033182, G9000147411, G9000184254, G9000210174, G9000264521
OpenAlex ID: W3009540687