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Smed-Evi/Wntless is required for beta-catenin-dependent and -independent processes during planarian regeneration. Development (Camb)

Department of Genetics and Institute of Biomedicine of the University of Barcelona, Barcelona, Spain.
Development (Impact Factor: 6.27). 03/2009; 136(6):905-10. DOI: 10.1242/dev.033761
Source: PubMed

ABSTRACT Planarians can regenerate a whole animal from only a small piece of their body, and have become an important model for stem cell biology. To identify regenerative processes dependent on Wnt growth factors in the planarian Schmidtea mediterranea (Smed), we analyzed RNAi phenotypes of Evi, a transmembrane protein specifically required for the secretion of Wnt ligands. We show that, during regeneration, Smed-evi loss-of-function prevents posterior identity, leading to two-headed planarians that resemble Smed-beta-catenin1 RNAi animals. In addition, we observe regeneration defects of the nervous system that are not found after Smed-beta-catenin1 RNAi. By systematic knockdown of all putative Smed Wnts in regenerating planarians, we identify Smed-WntP-1 and Smed-Wnt11-2 as the putative posterior organizers, and demonstrate that Smed-Wnt5 is a regulator of neuronal organization and growth. Thus, our study provides evidence that planarian Wnts are major regulators of regeneration, and that they signal through beta-catenin-dependent and -independent pathways.

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Available from: Kerstin Bartscherer, Mar 12, 2014
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    • "In planarians, flatworms with enormous regenerative potential (Gentile et al., 2011), the family of secreted Wnt proteins plays a crucial role during regeneration (Adell et al., 2009; Petersen and Reddien, 2009). When depleted of Smed-wnt1, a wnt gene initially expressed in cells at both anterior and posterior wounds, planarians regenerate heads instead of tails (Adell et al., 2009; Petersen and Reddien, 2009). In contrast, the secreted Wnt-inhibitor Notum is induced asymmetrically, mainly at anterior-facing wounds, and its knockdown generates two-tailed animals (Petersen and Reddien, 2011). "
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    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.
    Developmental Biology 06/2014; 390(2). DOI:10.1016/j.ydbio.2014.03.016 · 3.64 Impact Factor
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    • "To determine whether the impaired head regeneration observed after egr-4 RNAi was due to defects in the establishment of anterior polarity, we analyzed the expression of the anterior polarity determinants Smed-notum, Smed-wnt1 and Smed-follistatin (Adell et al., 2009; Gurley et al., 2010; Petersen and Reddien, 2009, 2011; Yazawa et al., 2009; Roberts-Galbraith and Newmark, 2013). Control animals exhibited three typical phases of Smed-notum expression (Fig. 4). "
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    ABSTRACT: During the regeneration of freshwater planarians, polarity and patterning programs play essential roles in determining whether a head or a tail regenerates at anterior or posterior-facing wounds. This decision is made very soon after amputation. The pivotal role of the Wnt/β-catenin and Hh signaling pathways in re-establishing anterior-posterior (AP) polarity has been well documented. However, the mechanisms that control the growth and differentiation of the blastema in accordance with its AP identity are less well understood. Previous studies have described a role of Smed-egfr-3, a planarian epidermal growth factor receptor, in blastema growth and differentiation. Here, we identify Smed-egr-4, a zinc-finger transcription factor belonging to the early growth response gene family, as a putative downstream target of Smed-egfr-3. Smed-egr-4 is mainly expressed in the central nervous system and its silencing inhibits anterior regeneration without affecting the regeneration of posterior regions. Single and combinatorial RNA interference to target different elements of the Wnt/β-catenin pathway, together with expression analysis of brain- and anterior-specific markers, revealed that Smed-egr-4: (1) is expressed in two phases - an early Smed-egfr-3-independent phase and a late Smed-egfr-3-dependent phase; (2) is necessary for the differentiation of the brain primordia in the early stages of regeneration; and (3) that it appears to antagonize the activity of the Wnt/β-catenin pathway to allow head regeneration. These results suggest that a conserved EGFR/egr pathway plays an important role in cell differentiation during planarian regeneration and indicate an association between early brain differentiation and the proper progression of head regeneration.
    Development 04/2014; 141(9). DOI:10.1242/dev.101345 · 6.27 Impact Factor
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    • "Smed-betaCatenin1(RNAi) in non-regenerating animals causes the conversion of the tail into a head and the emergence of ectopic heads all along the body edge (Gurley et al. 2008; Iglesias et al. 2008; Petersen and Reddien 2008). Gene expression patterns suggest permanently high canonical Wnt signaling in the tail and low levels in the head, as in the respective regeneration blastemas (Gurley et al. 2010; Petersen and Reddien 2009; Adell et al. 2009). β-Catenin and canonical Wnt signaling therefore exert the same highlevel lineage choices at steady state as during regeneration and the head-territory specific expression of Smed-prep in nonregenerating animals indicates the participation of similar factors. "
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    ABSTRACT: Planarians are members of the Platyhelminthes (flatworms). These animals have evolved a remarkable stem cell system. A single pluripotent adult stem cell type ("neoblast") gives rise to the entire range of cell types and organs in the planarian body plan, including a brain, digestive-, excretory-, sensory- and reproductive systems. Neoblasts are abundantly present throughout the mesenchyme and divide continuously. The resulting stream of progenitors and turnover of differentiated cells drive the rapid self-renewal of the entire animal within a matter of weeks. Planarians grow and literally de-grow ("shrink") by the food supply-dependent adjustment of organismal turnover rates, scaling body plan proportions over as much as a 50-fold size range. Their dynamic body architecture further allows astonishing regenerative abilities, including the regeneration of complete and perfectly proportioned animals even from tiny tissue remnants. Planarians as an experimental system, therefore, provide unique opportunities for addressing a spectrum of current problems in stem cell research, including the evolutionary conservation of pluripotency, the dynamic organization of differentiation lineages and the mechanisms underlying organismal stem cell homeostasis. The first part of this review focuses on the molecular biology of neoblasts as pluripotent stem cells. The second part examines the fascinating mechanistic and conceptual challenges posed by a stem cell system that epitomizes a universal design principle of biological systems: the dynamic steady state.
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