CEH-20/Pbx and UNC-62/Meis function upstream of rnt-1/Runx to regulate asymmetric divisions of the C. elegans stem-like seam cells

Abstract

SummaryCaenorhabditis elegans seam cells divide in the stem-like mode throughout larval development, with the ability to both self-renew and produce daughters that differentiate. Seam cells typically divide asymmetrically, giving rise to an anterior daughter that fuses with the hypodermis and a posterior daughter that proliferates further. Previously we have identified rnt-1 (a homologue of the mammalian cancer-associated stem cell regulator Runx) as being an important regulator of seam development, acting to promote proliferation; rnt-1 mutants have fewer seam cells whereas overexpressing rnt-1 causes seam cell hyperplasia. We isolated the interacting CEH-20/Pbx and UNC-62/Meis TALE-class transcription factors during a genome-wide RNAi screen for novel regulators of seam cell number. Animals lacking wild type CEH-20 or UNC-62 display seam cell hyperplasia, largely restricted to the anterior of the worm, whereas double mutants have many additional seam cells along the length of the animal. The cellular basis of the hyperplasia involves the symmetrisation of normally asymmetric seam cell divisions towards the proliferative stem-like fate. The hyperplasia is completely suppressed in rnt-1 mutants, and rnt-1 is upregulated in ceh-20 and unc-62 mutants, suggesting that CEH-20 and UNC-62 function upstream of rnt-1 to limit proliferative potential to the appropriate daughter cell. In further support of this we find that CEH-20 is asymmetrically localised in seam daughters following an asymmetric division, being predominantly restricted to anterior nuclei whose fate is to differentiate. Thus, ceh-20 and unc-62 encode crucial regulators of seam cell division asymmetry, acting via rnt-1 to regulate the balance between proliferation and differentiation.

The tumor suppressor APC differentially regulates multiple beta-catenins through the function of Axin and casein kinase 1alpha during C. elegans asymmetric stem cell divisions

“…The V5.p division occurs at the same time as the other Vn.p divisions; however, the anterior daughter of V5.p takes on a unique lineage that results in the birth of the PDE and PVD neurons, whereas the other Vn.pa cells continue the stereotyped seam cell lineage. Interestingly, although the Vn.p divisions (with the exception of V5.p) result in two seam cell daughters, it has been reported that APR-1, POP-1 and WRM-1 are all asymmetrically localized during this apparently cell-fatesymmetric division (Wildwater et al, 2011;Hughes et al, 2013). How the function and regulation of WbA signaling is different between the Vn.p division and the later seam cell divisions represents an interesting area of further study to determine how the function of Wnt signaling might change within a single stem cell lineage over time.…”

“…These visually accessible cells repeatedly divide asymmetrically in a stem-cell-like pattern during larval development, and cell fate determination for each of these divisions is dependent on the WbA pathway (supplementary material Fig. S1; Mizumoto and Sawa, 2007;Kanamori et al, 2008;Huang et al, 2009;Banerjee et al, 2010;Gleason and Eisenmann, 2010;Ren and Zhang, 2010;Harterink et al, 2011;Yamamoto et al, 2011;Gorrepati et al, 2013;Hughes et al, 2013). Thus, the lineage maintains a constant number of seam cells (posterior WbA-signaled daughters) while increasing the number of hypodermal nuclei (anterior Wnt-independent daughters).…”

C. elegans Runx/CBFβ suppresses POP-1(TCF) to convert asymmetric to proliferative division of stem cell-like seam cells

“…Wnt signaling and asymmetric localization of upstream pathway components restrict the repressor function to anterior cells, through export of POP-1 from the nucleus of posterior seam daughter cells (Takeshita & Sawa 2005), and by degrading the co-activator SYS-1 in the differentiating anterior daughters (Vora & Phillips 2015). Altered levels or localization defects of several Wnt/b-catenin asymmetry pathway components result in symmetric seam cell divisions, indicating the importance of this pathway for division asymmetry (Banerjee et al 2010;Gleason & Eisenmann 2010;Ren & Zhang 2010;Hughes et al 2013). Whether and how symmetric seam cell divisions circumvent the Wnt/b-catenin asymmetry pathway is currently not understood.…”

Unique and redundant β-catenin regulatory roles of two Dishevelled paralogs during C. elegans asymmetric cell division

“…WβA signaling has been shown to control cell fate in the asymmetric cell divisions of the C. elegans hypodermal seam cells (Banerjee et al, 2010;Gleason and Eisenmann, 2010;Gorrepati et al, 2013;Hughes et al, 2013;Ren and Zhang, 2010;Yamamoto et al, 2011). The C. elegans seam is composed of two lines of hypodermal cells, one each on the left and right sides of the worm.…”

“…To do this, we combined both Dvl mutants with the osIs5 (P scm ::WRM-1::YFP) transgene that we and others have previously reported to localize asymmetrically to seam cell daughter nuclei (Baldwin and Phillips, 2014;Hughes et al, 2013;Mizumoto and Sawa, 2007). mig-5 mutants displayed a significant reduction in average nuclear WRM-1 levels in the posterior daughter nucleus, indicating that MIG-5 positively regulates WRM-1 levels in that daughter (Fig.…”