Actin-based deformations of the nucleus control multiciliated ependymal cell differentiation

Abstract

ABSTRACTEpendymal cells (ECs) are multi-ciliated cells in the brain that contribute to cerebrospinal fluid flow. ECs are specified at embryonic stages but differentiate and grow cilia later in development. Differentiation depends on genes such as GEMC1 and MCIDAS with E2F4/5 but also on cell cycle related factors. In the mouse brain, we observe that nuclear deformation accompanies EC differentiation. Tampering with these deformations either by decreasing F-actin levels or by severing the link between the nucleus and the actin cytoskeleton blocks differentiation. Conversely, increasing F-actin by knocking out the Arp2/3 complex inhibitor Arpin activates differentiation. Thus, actin polymerization triggers nuclear deformation and jump-starts the signaling that produce differentiated ECs. We show evidence that one of the players in this process is the retinoblastoma 1 (RB1) protein whose phosphorylation prompts MCIDAS activation. Overall, this study reveals an important role for actin-based mechanical inputs to the nucleus as controlling factors in cell differentiation.