Filamin A- and formin 2-dependent endocytosis regulates proliferation via the canonical Wnt pathway

• DOI: 10.1242/dev.139295
• Publication Date: 2016-10-28T00:48:54Z
• Authors: Gewei Lian; Markus Dettenhofer; Jie Lu; Michael Downing; Anjen Chenn; Timothy Wong; Volney Sheen
• Keywords: Mice, Knockout; 0301 basic medicine; Glycogen Synthase Kinase 3 beta; Filamins; Cell Membrane; Microfilament Proteins; Formins; Nuclear Proteins; Cell Differentiation; Nerve Tissue Proteins; Endocytosis; Cell Line; Wnt Proteins; Mice; 03 medical and health sciences; HEK293 Cells; Low Density Lipoprotein Receptor-Related Protein-6; Microcephaly; Animals; Humans; Wnt Signaling Pathway; Cell Proliferation

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.