title: Filamin A- and formin 2-dependent endocytosis regulates proliferation via the canonical Wnt pathway.
abstract: Actin-associated proteins regulate multiple cellular processes, including proliferation and differentiation, but the molecular mechanisms underlying these processes are unclear. Here, we report that the actin-binding protein filamin A (FlnA) physically interacts with the actin-nucleating protein formin 2 (Fmn2). Loss of FlnA and Fmn2 impairs proliferation, thereby generating multiple embryonic phenotypes, including microcephaly. FlnA interacts with the Wnt co-receptor Lrp6. Loss of FlnA and Fmn2 impairs Lrp6 endocytosis, downstream Gsk3β activity, and β-catenin accumulation in the nucleus. The proliferative defect in Flna and Fmn2 null neural progenitors is rescued by inhibiting Gsk3β activity. Our findings thus reveal a novel mechanism whereby actin-associated proteins regulate proliferation by mediating the endocytosis and transportation of components in the canonical Wnt pathway. Moreover, the Fmn2-dependent signaling in this pathway parallels that seen in the non-canonical Wnt-dependent regulation of planar cell polarity through the Formin homology protein Daam. These studies provide evidence for integration of actin-associated processes in directing neuroepithelial proliferation.
authors: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors: Gewei
authors: G
authors: Lian
authors: Central European Institute of Technology, Žerotínovo nám. 9, Brno 601 77, Czech Republic.
authors: Markus
authors: M
authors: Dettenhofer
authors: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors: Jie
authors: J
authors: Lu
authors: Department of Pathology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors: Michael
authors: M
authors: Downing
authors: Department of Pathology, University of Illinois College of Medicine, Chicago, IL 60612, USA.
authors: Anjen
authors: A
authors: Chenn
authors: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
authors: Timothy
authors: T
authors: Wong
authors: Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA vsheen@bidmc.harvard.edu.
authors: Volney
authors: 0000-0002-7931-8200
authors: V
authors: Sheen
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology*; D064448:Filamins / Q000235:genetics / Q000378:metabolism*; D000080865:Formins; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008831:Microcephaly / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D064448:Filamins; C529499:FlnA protein, mouse; D000080865:Formins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C549436:formin 2 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Differentiation; Endocytosis; Filamin; Formin; Lrp6; Neural progenitor; Proliferation; Vesicle trafficking