Desert hedgehog-primary cilia cross talk shapes mitral valve tissue by organizing smooth muscle actin. - Biology of Cardiovascular Diseases Accéder directement au contenu
Article Dans Une Revue Developmental Biology Année : 2020

Desert hedgehog-primary cilia cross talk shapes mitral valve tissue by organizing smooth muscle actin.

Joshua H Lipschutz
  • Fonction : Auteur

Résumé

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.
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Dates et versions

hal-03159130 , version 1 (04-03-2021)

Identifiants

Citer

Diana Fulmer, Katelynn A Toomer, Janiece Glover, Lilong Guo, Kelsey Moore, et al.. Desert hedgehog-primary cilia cross talk shapes mitral valve tissue by organizing smooth muscle actin.. Developmental Biology, 2020, 463 (1), pp.26-38. ⟨10.1016/j.ydbio.2020.03.003⟩. ⟨hal-03159130⟩

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