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Recent genetic studies have begun to unravel the complexities of MVP and through these efforts, mutations in the FLNA (Filamin\u2010A) gene were identified as disease causing. Our <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> studies have validated these genetic findings and have revealed FLNA as a central regulator of valve morphogenesis. The mechanisms by which FLNA mutations result in myxomatous mitral valve disease are currently unknown, but may involve proteins previously associated with mutated regions of the FLNA protein, such as the small GTPase signaling protein, R\u2010Ras. Herein, we report that Filamin\u2010A is required for R\u2010Ras expression and activation of the Ras\u2013Mek\u2013Erk pathway. Loss of the Ras\/Erk pathway correlated with hyperactivation of pSmad2\/3, increased extracellular matrix (ECM) production and enlarged mitral valves. Analyses of integrin receptors in the mitral valve revealed that Filamin\u2010A was required for \u03b21\u2010integrin expression and provided a potential mechanism for impaired ECM compaction and valve enlargement. Our data support Filamin\u2010A as a protein that regulates the balance between Erk and Smad activation and an inability of Filamin\u2010A deficient valve interstitial cells to effectively remodel the increased ECM production through a \u03b21\u2010integrin mechanism. As a consequence, loss of Filamin\u2010A function results in increased ECM production and generation of a myxomatous phenotype characterized by improperly compacted mitral valve tissue. Anat Rec, 302:117\u2013124, 2019. \u00a9 2018 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/ar.23911","type":"journal-article","created":{"date-parts":[[2018,10,6]],"date-time":"2018-10-06T01:50:20Z","timestamp":1538790620000},"page":"117-124","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Filamin\u2010A as a Balance between Erk\/Smad Activities During Cardiac Valve Development"],"prefix":"10.1002","volume":"302","author":[{"given":"Katelynn","family":"Toomer","sequence":"first","affiliation":[{"name":"Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, College of Medicine, Children's Research Institute Medical University of South Carolina  Charleston South Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Sauls","sequence":"additional","affiliation":[{"name":"Cardiovascular Developmental Biology Center, Department of 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