Stem cell-dependent formation of a functional anterior regeneration pole in planarians requires Zic and Forkhead transcription factors

Abstract

Planarians can regenerate their head within days. This process depends on the direction of adult stem cells to wound sites and the orchestration of their progenitors to commit to appropriate lineages and to arrange into patterned tissues. We identified a zinc finger transcription factor, Smed-ZicA, as a downstream target of Smed-FoxD, a Forkhead transcription factor required for head regeneration. Smed-zicA and Smed-FoxD are co-expressed with the Wnt inhibitor notum and the Activin inhibitor follistatin in a cluster of cells at the anterior-most tip of the regenerating head - the anterior regeneration pole - and in surrounding stem cell progeny. Depletion of Smed-zicA and Smed-FoxD by RNAi abolishes notum and follistatin expression at the pole and inhibits head formation downstream of initial polarity decisions. We suggest a model in which ZicA and FoxD transcription factors synergize to control the formation of Notum- and Follistatin-producing anterior pole cells. Pole formation might constitute an early step in regeneration, resulting in a signaling center that orchestrates cellular events in the growing tissue.

Localization of planarian β-CATENIN-1 reveals multiple roles during anterior-posterior regeneration and organogenesis

“…Considering that not only the tip-related expression of notum but also the brainrelated expression completely disappears after β-catenin-1 RNAi, notum may be directly regulated by β-catenin-1, generating a regulatory loop to control β-catenin-1 levels in the anterior region of planarians (Hill and Petersen, 2015;Petersen and Reddien, 2011;Scimone et al, 2014). Our findings thus support three major roles of β-catenin-1 in anterior regeneration: (1) the specification and maintenance of the anterior signaling center, defined by the tiprelated expression of notum (Petersen and Reddien, 2011) and other genes (Chen et al, 2013;Gaviño et al, 2013;Roberts-Galbraith and Newmark, 2013;Scimone et al, 2014;Vásquez-Doorman and Petersen, 2014;Vogg et al, 2014) (Fig. 6A,B); (2) the regeneration of the brain, through the regulation of the brain-related expression of notum (Hill and Petersen, 2015); and (3) the specification of different neuronal cell types, as described in most animal models (Ciani and Salinas, 2005;Hari et al, 2002;Lewis et al, 2004;Machon et al, 2003;Watanabe et al, 2014;Yu and Malenka, 2003;Zechner et al, 2003).…”

teashirt is required for head-versus-tail regeneration polarity in planarians

“…Anterior and posterior poles are small clusters of cells at the head and tail tip, respectively, and are required for normal planarian head and tail regeneration and PCG expression (Felix and Aboobaker, 2010;Hayashi et al, 2011;Blassberg et al, 2013;Chen et al, 2013;Scimone et al, 2014b;Vásquez-Doorman and Petersen, 2014;Vogg et al, 2014). However, in contrast to teashirt RNAi, inhibition of either anterior or posterior pole formation does not cause a reversal of the head-tail regeneration choice.…”

Wnt/Notum spatial feedback inhibition controls neoblast differentiation to regulate reversible growth of the planarian brain

“…Neoblasts are a heterogeneous population that includes both pluripotent cells and distinct subpopulations specified for production of multiple differentiated tissues (Adler et al, 2014;Cowles et al, 2013;Currie and Pearson, 2013;Forsthoefel et al, 2012;Lapan and Reddien, 2012;Marz et al, 2013;Scimone et al, 2011Scimone et al, , 2014avan Wolfswinkel et al, 2014;Vásquez-Doorman and Petersen, 2014;Vogg et al, 2014;Wenemoser et al, 2012). We hypothesized that notum and wnt11-6 might regulate brain cell production by controlling numbers of brain cell progenitors marked by expression of lineage-specific transcription factors.…”

“…Growth from feeding or epimorphic regeneration depends on parenchymal cells termed neoblasts that are the only proliferating cells in adult planarians (Baguñà, 1976;Newmark and Sánchez Alvarado, 2000;Reddien et al, 2005b). Neoblasts are a heterogeneous population containing both adult pluripotent stem cells (Wagner et al, 2011) and more lineage-restricted dividing cells (Adler et al, 2014;Cowles et al, 2013;Currie and Pearson, 2013;Forsthoefel et al, 2012;Lapan and Reddien, 2012;Marz et al, 2013;Scimone et al, 2014aScimone et al, ,b, 2011van Wolfswinkel et al, 2014;Vásquez-Doorman and Petersen, 2014;Vogg et al, 2014;Wenemoser et al, 2012). Tissue removal results in proliferative activation of neoblasts thought to be necessary for production of missing tissue types within the regeneration blastema.…”