FilaminA and Formin2 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 FilaminA physically interacts with the actin-nucleating protein Formin2. Loss of FilaminA and Formin2 impairs proliferation, thereby generating multiple embryonic phenotypes, including microcephaly. FilaminA interacts with the Wnt co-receptor Lrp6. Loss of FilaminA and Formin2 impairs Lrp6 endocytosis, downstream Gsk3β activity, and β-catenin accumulation in the nucleus. Finally, the proliferative defect in null FilaminA and Formin2 neural progenitors is rescued by inhibiting Gsk3β activity. Our findings provide an unrealized mechanism whereby actin-associated endocytosis regulates proliferation by mediating molecules in the canonical Wnt pathway. Moreover, the Formin2-dependent signaling in this pathway parallels that seen in the non-canonical Wnt-dependent regulation of planar cell polarity through the Formin homology Daam protein. These studies provide evidence for integration of actin-associated processes in directing neuroepithelial proliferation.