title: Developmental basis for filamin-A-associated myxomatous mitral valve disease.
abstract: OBJECTIVE
  We hypothesized that the structure and function of the mature valves is largely dependent upon how these tissues are built during development, and defects in how the valves are built can lead to the pathological progression of a disease phenotype. Thus, we sought to uncover potential developmental origins and mechanistic underpinnings causal to myxomatous mitral valve disease. We focus on how filamin-A, a cytoskeletal binding protein with strong links to human myxomatous valve disease, can function as a regulatory interface to control proper mitral valve development.
  
  
  RESULTS
  Filamin-A-deficient mice exhibit abnormally enlarged mitral valves during foetal life, which progresses to a myxomatous phenotype by 2 months of age. Through expression studies, in silico modelling, 3D morphometry, biochemical studies, and 3D matrix assays, we demonstrate that the inception of the valve disease occurs during foetal life and can be attributed, in part, to a deficiency of interstitial cells to efficiently organize the extracellular matrix (ECM). This ECM organization during foetal valve gestation is due, in part, to molecular interactions between filamin-A, serotonin, and the cross-linking enzyme, transglutaminase-2 (TG2). Pharmacological and genetic perturbations that inhibit serotonin-TG2-filamin-A interactions lead to impaired ECM remodelling and engender progression to a myxomatous valve phenotype.
  
  
  CONCLUSIONS
  These findings illustrate a molecular mechanism by which valve interstitial cells, through a serotonin, TG, and filamin-A pathway, regulate matrix organization during foetal valve development. Additionally, these data indicate that disrupting key regulatory interactions during valve development can set the stage for the generation of postnatal myxomatous valve disease.
authors: Department of Regenerative Medicine and Cell Biology, School of Medicine, Cardiovascular Developmental Biology Center, Children's Research Institute,  Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425,  USA.
authors: Kimberly
authors: K
authors: Sauls
authors: Annemarieke
authors: A
authors: de Vlaming
authors: Brett S
authors: BS
authors: Harris
authors: Katherine
authors: K
authors: Williams
authors: Andy
authors: A
authors: Wessels
authors: Robert A
authors: RA
authors: Levine
authors: Susan A
authors: SA
authors: Slaugenhaupt
authors: Richard L
authors: RL
authors: Goodwin
authors: Luigi Michele
authors: LM
authors: Pavone
authors: Jean
authors: J
authors: Merot
authors: Jean-Jacques
authors: JJ
authors: Schott
authors: Thierry
authors: T
authors: Le Tourneau
authors: Thomas
authors: T
authors: Dix
authors: Sean
authors: S
authors: Jesinkey
authors: Yuanyi
authors: Y
authors: Feng
authors: Christopher
authors: C
authors: Walsh
authors: Bin
authors: B
authors: Zhou
authors: Scott
authors: S
authors: Baldwin
authors: Roger R
authors: RR
authors: Markwald
authors: Russell A
authors: RA
authors: Norris
mesh_terms: D000818:Animals; D003285:Contractile Proteins / Q000235:genetics / Q000378:metabolism*; D064448:Filamins; D019204:GTP-Binding Proteins / Q000378:metabolism; D040181:Genetic Diseases, X-Linked / Q000196:embryology* / Q000235:genetics; D006330:Heart Defects, Congenital / Q000196:embryology* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008943:Mitral Valve / Q000196:embryology*; D008945:Mitral Valve Prolapse / Q000196:embryology* / Q000235:genetics; D009232:Myxoma / Q000196:embryology* / Q000235:genetics; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D011503:Transglutaminases / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism
chemical_list: D003285:Contractile Proteins; D064448:Filamins; D008840:Microfilament Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins