{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FHOD3 is a conserved formin family protein that plays a central role in organizing the actin cytoskeleton by nucleating and elongating straight actin filaments in a variety of cellular contexts. In the heart, FHOD3 is indispensable for proper sarcomere assembly and myofibril maintenance. Genetic studies have linked both common polymorphisms and rare mutations—including nonsynonymous changes (e.g., V1151I and p.S527del) and splicing variants—to hypertrophic and dilated cardiomyopathies, underscoring its importance for normal contractile function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": " Moreover, post‐translational modifications—such as phosphorylation by ROCK and CK2—regulate FHOD3’s subcellular localization and activity, thereby modulating actin-driven myofibrillogenesis and contributing to maladaptive cardiac remodeling under stress."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Outside the heart, FHOD3 has been implicated in other actin-dependent processes. In cancer cells, for example, FHOD3 is activated by RhoA/ROCK signaling to promote the formation of Arp2/3–independent, filopodial actin spike protrusions that facilitate invasive migration in three-dimensional extracellular matrices."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In addition, FHOD3-mediated actin assembly is critical during mammalian neurulation; it drives apical constriction in lateral neural plate cells, contributing both to neural tube closure and to the segmentation of hindbrain structures."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Regulation of FHOD3 activity in cardiomyocytes is further refined by alternative splicing. RNA-binding proteins such as RBM20 and PTBP1 mediate an isoform switch that affects FHOD3’s role in organizing actin filaments, with potential implications for cardiac disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}, {"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Structural analyses reveal that FHOD3 shares a canonical domain architecture—with conserved FH1 and FH2 regions augmented by newly identified conserved elements (FHDHN and FHDHC)—that it shares with related formins in diverse species."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Collectively, these findings demonstrate that FHOD3’s ability to regulate actin assembly is critical to both normal development and tissue homeostasis as well as to disease processes ranging from cardiomyopathy to cancer invasion.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Eric C Wooten, Virginia B Hebl, Matthew J Wolf, et al. 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