Seminars

Nuclear positioning is central to many cellular and developmental events. A bridge of inner nuclear membrane (INM) SUN proteins and outer nuclear membrane (ONM) KASH proteins spans the nuclear envelope. In C. elegans, the SUN protein UNC-84 recruits the KASH protein UNC-83 to the ONM where it targets dynein and kinesin-1 to move nuclei along a polarized microtubule network. However, it remains unknown how SUN proteins span the perinuclear space of the nuclear envelope and how forces transferred across the bridge are dissipated at the nucleoskeleton. We identified an interaction between UNC-84 and the lamin B gene LMN-1. lmn-1(RNAi) animals had a hyp7 nuclear migration defect. Moreover, the LMN-1 interaction was significantly weakened by an UNC-84 P91S mutation that was previously identified in genetic screens with a partial loss-of-function nuclear migration defect. These data support a model where UNC-84 interacts with LMN-1 to dissipate force from the bridge to the nucleoskeleton. To test the hypothesis that UNC-84 spans and regulates the space between the INM and ONM, we examined the morphology of the nuclear envelope by electron microscopy in unc- 84(null) mutants. We observed extreme separation of the ONM from the INM in unc- 84(null) L1 muscle nuclei. Surprisingly, a truncated form of UNC84 is able to stretch between the two nuclear membranes. Finally, we have developed a system to study nuclear migration through constrained spaces similar to how some metastatic cells migrate. We have elucidated the mechanisms of two pathways that work together to move C. elegans P-cell nuclei that are conserved to mice. In the first pathway, SUN and KASH membrane proteins form a bridge across the nuclear envelope and recruit dynein to provide the major force to move nuclei. To identify a second pathway, we have employed a forward genetic screen to identify enhancers of the nuclear migration defect of unc-83/84 (emu) genes. The emu pathway contains the actin organizers TOCA-1 and FLN-2; defects in FLN-2 disrupt the actin cables usually observed in P-cells during nuclear migration. Our studies show that microtubule and actin networks function together to move nuclei.