FULMER, Diana; TOOMER, Katelynn A.; GLOVER, Janiece; GUO, Lilong; MOORE, Kelsey; MOORE, Reece; STAIRLEY, Rebecca; GENSEMER, Cortney; ABROL, Sameer; RUMPH, Mary Kate; EMETU, Faith; LIPSCHUTZ, Joshua; MCDOWELL, Colin; BIAN, Justin; WANG, Christina; BECK, Tyler; WESSELS, Andy; RENAULT, Marie-Ange; NORRIS, Russell

doi:10.1016/j.ydbio.2020.03.003

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Article de revue

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Developmental Biology. 2020

Résumé en anglais

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.< Réduire

Mots clés en anglais

Actins

Animals

Cilia

Extracellular Matrix

Heart Valve Diseases

Hedgehog Proteins

Mice

Mitral Valve

Mitral Valve Prolapse

Muscle

Smooth

Myocytes

Smooth Muscle

Neuropeptides

Phenotype

Signal Transduction

Transcription Factors

rac1 GTP-Binding Protein

URI

https://oskar-bordeaux.fr/handle/20.500.12278/11438

DOI

http://dx.doi.org/10.1016/j.ydbio.2020.03.003

Unités de recherche

Biologie des maladies cardiovasculaires (BMC) - UMR 1034

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Desert Hedgehog-Primary Cilia Cross Talk Shapes Mitral Valve Tissue by Organizing Smooth Muscle Actin

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Résumé en anglais

Mots clés en anglais

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Unités de recherche