The ability of cells to traverse basement membranes is a key part of fertility, development, immunity, and disease. Basement membrane remodeling during C. elegans uterine-vulval morphogenesis provides a tractable and visually amenable model in which to study this cellular behavior in vivo. The anchor cell (AC), a specialized uterine cell, invades through the underlying basement membrane utilizing a combination of extrinsic cues and an intrinsic gene regulatory network (GRN) that regulates expression of matrix metalloproteinases and polarization of the F-actin cytoskeleton. Coordination of these invasive programs is largely achieved through regulation of gene expression by transcription factors (TFs) whose effectors and interactors have been previously characterized, including the basic leucine zipper TF
fos-1a (Fos), the basic helix-loop-helix TF
hlh-2 (E/Daughterless), as well as the long isoform of the zinc-finger TF,
egl-43a (EVI1/MEL1). Additionally, prior work from our lab shows that cell invasion and proliferation are mutually exclusive behaviors. The conserved nuclear hormone receptor
nhr-67 (TLX/NR2E1) is required in the AC to maintain a CKI-1 (
p21/p27) dependent G1/G0-cell cycle arrest necessary for invasive activity. How this cell cycle-dependent pathway interfaces with the known pro-invasive GRN is not well understood. Using endogenous GFP-tagged reporters and protein depletion tools visualized with high-resolution quantitative fluorescent microscopy, we confirm previous work demonstrating that
egl-43 (EVI1/MEL1) regulates
nhr-67 activity in the AC. We are also investigating the function of the two isoforms of
egl-43 in modulating AC invasion, in relation to both
nhr-67-mediated cell cycle arrest and the
fos-1a-driven basement membrane removal pathways. Finally, we demonstrate that ectopic expression of NHR-67 is sufficient to induce invasiveness in neighboring non-invasive cells, identifying NHR-67 as a key node in establishing an invasion program. Together, these results provide the first characterization of the GRN that underlies cell cycle control of invasive differentiation.