| First Author | Fulmer D | Year | 2020 |
| Journal | Dev Biol | Volume | 463 |
| Issue | 1 | Pages | 26-38 |
| PubMed ID | 32151560 | Mgi Jnum | J:290862 |
| Mgi Id | MGI:6438280 | Doi | 10.1016/j.ydbio.2020.03.003 |
| Citation | Fulmer D, et al. (2020) Desert hedgehog-primary cilia cross talk shapes mitral valve tissue by organizing smooth muscle actin. Dev Biol 463(1):26-38 |
| abstractText | 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 alpha-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. |
