Transcriptional regulation and repressive condensates modulate a proliferative-invasive cellular switch in vivo

A growing body of evidence suggests that cell division and basement membrane invasion are mutually exclusive cellular behaviors. How cells switch between proliferative and invasive states is not well understood. Here, we investigated this dichotomy in vivo by examining two cell types that derive from equipotent progenitors, but exhibit distinct cell behaviors, in the developing Caenorhabditis elegans somatic gonad: the post-mitotic, invasive anchor cell and the neighboring proliferative, non-invasive ventral uterine (VU) cells. We report that the default invasive cellular state is suppressed in the VU cells through two distinct modes of regulation of the pro-invasive transcription factor NHR-67 (NR2E1/TLX). Levels of NHR-67 are important for discriminating between invasive and proliferative behavior, and nhr-67 transcription is downregulated following post-translational degradation of its direct upstream regulator, HLH-2 (E/Daughterless) in VU cells. Residual NHR-67 protein is organized into discrete punctae in the nuclei of VU cells that are dynamic over the cell cycle and exhibit liquid-like properties. Strikingly, these NHR-67 punctae are not spatiotemporally associated with active transcription, but instead associate with homologs of the transcriptional co-repressor Groucho (UNC-37 and LSY-22), as well as the TCF/LEF homolog POP-1, likely mediated by a direct interaction between UNC-37 and the intrinsically disordered region of NHR-67. Further, perturbing UNC-37, LSY-22, or POP-1 results in ectopic invasive cells. We propose a model in which these proteins together form repressive condensates to suppress a default invasive state in non-invasive cells, which complements transcriptional regulation to add robustness to the proliferative-invasive cellular switch in vivo . ### Competing Interest Statement David Q. Matus and Neha Somineni are paid employees of Arcadia Science and Integra LifeSciences, respectively.