Seam cells divide asymmetrically, typically producing an anterior daughter that differentiates and a posterior daughter that proliferates further, although there are deviations from this pattern. The asymmetric outcome of these divisions is controlled by the Wnt/b-catenin asymmetry (WBA) pathway, with the b-catenin WRM-1 being enriched at the anterior cortex and posterior daughter nuclei at division. In addition,
rnt-1 (the homologue of the mammalian cancer-associated Runx genes) is thought to act in parallel to the WBA pathway, being preferentially expressed in posterior daughters where it promotes the proliferative fate. We isolated the interacting CEH-20/Pbx and UNC-62/Meis transcription factors during a genome-wide RNAi screen for novel regulators of seam cell number.
ceh-20 and
unc-62 mutants display seam cell hyperplasia caused by the symmetrisation of normally asymmetric seam cell divisions towards the proliferative stem-like fate. Although WRM-1 localisation is perturbed in
ceh-20(RNAi) animals, the hyperplasia is not dependent on WRM-1, suggesting that CEH-20/UNC-62 function downstream of or in parallel to Wnt signalling. Interestingly, in wild type animals, we observed that WRM-1 is always enriched at the anterior cortex and posterior nucleus during all seam cell divisions, even the symmetrical divisions occurring at L2 and in anterior L1 divisions where polarity is reversed. Thus, WRM-1 (and POP-1) asymmetry is somehow over-ridden in seam cell divisions that do not follow the canonical pattern. The
ceh-20/unc-62 hyperplasia is completely suppressed in
rnt-1 mutants, suggesting that CEH-20 and UNC-62 function upstream of
rnt-1 to limit proliferative potential to the appropriate daughter cell. Our data suggest that CEH-20/UNC-62 normally down-regulate
rnt-1 in anterior daughters that are destined to exit from the cell cycle and terminally differentiate. Furthermore, we find that CEH-20 is asymmetrically localised in seam daughters following an asymmetric division, being predominantly restricted to anterior nuclei. Thus, we have identified
ceh-20 and
unc-62 as crucial regulators of seam cell development, acting via
rnt-1 to regulate the balance between proliferation and differentiation.