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• W2594920429 abstract "•Eye regeneration occurs without regulation of planarian stem cells by the eye•Decreased cell death in regenerating eyes facilitates tissue-specific regeneration•Large head injuries without eye removal increased eye progenitor formation•Eye absence is not sufficient or necessary for increased eye progenitor production Dividing cells called neoblasts contain pluripotent stem cells and drive planarian flatworm regeneration from diverse injuries. A long-standing question is whether neoblasts directly sense and respond to the identity of missing tissues during regeneration. We used the eye to investigate this question. Surprisingly, eye removal was neither sufficient nor necessary for neoblasts to increase eye progenitor production. Neoblasts normally increase eye progenitor production following decapitation, facilitating regeneration. Eye removal alone, however, did not induce this response. Eye regeneration following eye-specific resection resulted from homeostatic rates of eye progenitor production and less cell death in the regenerating eye. Conversely, large head injuries that left eyes intact increased eye progenitor production. Large injuries also non-specifically increased progenitor production for multiple uninjured tissues. We propose a model for eye regeneration in which eye tissue production by planarian stem cells is not directly regulated by the absence of the eye itself. Dividing cells called neoblasts contain pluripotent stem cells and drive planarian flatworm regeneration from diverse injuries. A long-standing question is whether neoblasts directly sense and respond to the identity of missing tissues during regeneration. We used the eye to investigate this question. Surprisingly, eye removal was neither sufficient nor necessary for neoblasts to increase eye progenitor production. Neoblasts normally increase eye progenitor production following decapitation, facilitating regeneration. Eye removal alone, however, did not induce this response. Eye regeneration following eye-specific resection resulted from homeostatic rates of eye progenitor production and less cell death in the regenerating eye. Conversely, large head injuries that left eyes intact increased eye progenitor production. Large injuries also non-specifically increased progenitor production for multiple uninjured tissues. We propose a model for eye regeneration in which eye tissue production by planarian stem cells is not directly regulated by the absence of the eye itself. Regeneration is the replacement of body parts lost to injury, such as organs or appendages, and occurs throughout the animal kingdom (Poss, 2010Poss K.D. Advances in understanding tissue regenerative capacity and mechanisms in animals.Nat. Rev. Genet. 2010; 11: 710-722Crossref PubMed Scopus (286) Google Scholar, Sánchez Alvarado, 2000Sánchez Alvarado A. Regeneration in the metazoans: why does it happen?.Bioessays. 2000; 22: 578-590Crossref PubMed Scopus (229) Google Scholar, Tanaka and Reddien, 2011Tanaka E.M. Reddien P.W. The cellular basis for animal regeneration.Dev. Cell. 2011; 21: 172-185Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar). How animals respond to the absence of specific tissues following injury to bring about their precise replacement is a central but poorly understood problem in regeneration biology. Planarians are free-living flatworms that can regenerate from almost any injury, making them a powerful model for the study of animal regeneration (Reddien and Sánchez Alvarado, 2004Reddien P.W. Sánchez Alvarado A. Fundamentals of planarian regeneration.Annu. Rev. Cell Dev. Biol. 2004; 20: 725-757Crossref PubMed Scopus (528) Google Scholar). Underlying this regenerative ability is a proliferative population of cells called neoblasts that contain pluripotent stem cells (Wagner et al., 2011Wagner D.E. Wang I.E. Reddien P.W. Clonogenic neoblasts are pluripotent adult stem cells that underlie planarian regeneration.Science. 2011; 332: 811-816Crossref PubMed Scopus (440) Google Scholar). Neoblasts constitute the only dividing adult somatic planarian cells and are required for the regeneration and homeostatic maintenance of all differentiated tissues. A remarkable aspect of planarian regeneration is that it is tissue specific; whether an injury removes an entire section of the body, or specifically ablates a single tissue of virtually any type, the animal replaces precisely those tissues that were lost (Adler et al., 2014Adler C.E. Seidel C.W. McKinney S.A. Sánchez Alvarado A. Selective amputation of the pharynx identifies a FoxA-dependent regeneration program in planaria.Elife. 2014; 3: e02238Crossref Scopus (25) Google Scholar, Nishimura et al., 2011Nishimura K. Inoue T. Yoshimoto K. Taniguchi T. Kitamura Y. Agata K. Regeneration of dopaminergic neurons after 6-hydroxydopamine-induced lesion in planarian brain.J. Neurochem. 2011; 119: 1217-1231Crossref PubMed Scopus (37) Google Scholar, Reddien and Sánchez Alvarado, 2004Reddien P.W. Sánchez Alvarado A. Fundamentals of planarian regeneration.Annu. Rev. Cell Dev. Biol. 2004; 20: 725-757Crossref PubMed Scopus (528) Google Scholar). One hypothesis to explain this highly specific nature of planarian regeneration is that neoblasts sense the presence and absence of specific tissues after injury, modifying their output in accordance with the identity of missing tissues (Adler and Sánchez Alvarado, 2015Adler C.E. Sánchez Alvarado A. Types or states? Cellular dynamics and regenerative potential.Trends Cell Biol. 2015; 25: 687-696Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, Mangel et al., 2016Mangel M. Bonsall M.B. Aboobaker A. Feedback control in planarian stem cell systems.BMC Syst. Biol. 2016; 10: 17Crossref PubMed Scopus (3) Google Scholar, Nishimura et al., 2011Nishimura K. Inoue T. Yoshimoto K. Taniguchi T. Kitamura Y. Agata K. Regeneration of dopaminergic neurons after 6-hydroxydopamine-induced lesion in planarian brain.J. Neurochem. 2011; 119: 1217-1231Crossref PubMed Scopus (37) Google Scholar). However, whether neoblast output is directly regulated by the presence or absence of the specific tissues to be regenerated is unclear. Planarian eyes present an ideal venue to investigate the mechanistic basis of tissue-specific regeneration in vivo. The paired planarian eyes, which can be formed de novo after head amputation, are simple organs composed of pigmented optic cup cells and photoreceptor neurons (PRNs) that connect to a bilobed brain. The eyes are discretely located, visible in live animals, and dispensable for viability, making them good targets for specific surgical manipulation. Molecular characterization has identified tissue-specific markers for eye cell types and provided tools for the visualization of eye progenitors during regeneration (Lapan and Reddien, 2011Lapan S.W. Reddien P.W. dlx and sp6-9 control optic cup regeneration in a prototypic eye.PLoS Genet. 2011; 7: e1002226Crossref PubMed Scopus (102) Google Scholar, Lapan and Reddien, 2012Lapan S.W. Reddien P.W. Transcriptome analysis of the planarian eye identifies ovo as a specific regulator of eye regeneration.Cell Rep. 2012; 2: 294-307Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, Sánchez Alvarado and Newmark, 1999Sánchez Alvarado A. Newmark P.A. Double-stranded RNA specifically disrupts gene expression during planarian regeneration.Proc. Natl. Acad. Sci. USA. 1999; 96: 5049-5054Crossref PubMed Scopus (446) Google Scholar). Previously, we found that head amputation leads to the formation of a large number of specialized neoblasts expressing eye-associated transcription factors. These eye-specialized neoblasts give rise to progenitors that migrate anteriorly, progressively differentiate, and coalesce to form the regenerated eyes (Lapan and Reddien, 2011Lapan S.W. Reddien P.W. dlx and sp6-9 control optic cup regeneration in a prototypic eye.PLoS Genet. 2011; 7: e1002226Crossref PubMed Scopus (102) Google Scholar, Lapan and Reddien, 2012Lapan S.W. Reddien P.W. Transcriptome analysis of the planarian eye identifies ovo as a specific regulator of eye regeneration.Cell Rep. 2012; 2: 294-307Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). The potential for inducing tissue-specific injuries combined with the ability to observe the cellular stages of eye regeneration presented a unique opportunity to investigate the mechanistic basis of tissue-specific regeneration. To directly test the hypothesis that neoblasts are regulated by the presence or absence of eye tissue, we examined eye progenitor responses to tissue-specific eye resection and to various large injuries that either removed the eyes or left the eyes uninjured. Surprisingly, our data demonstrate that stem cell-based eye progenitor production is not regulated by the presence or absence of the eye itself. Specific removal of the eye did not affect eye progenitor production. Instead, less cell death occurred in regenerating eyes, allowing them to grow in size despite no specific increase in the rate of eye progenitor production. Such a passive process could fuel regeneration from a myriad of injuries removing different cell types. Eye absence was also not necessary for increased eye progenitor formation. Increased eye progenitor formation was induced whenever large injuries triggered general neoblast proliferation in the body position where eye progenitor specification occurs, regardless of the presence or absence of the eyes. Large injuries also non-specifically increased the production of uninjured pharynx and ventral nerve cord tissue. We propose a “target-blind” progenitor model for planarian eye regeneration, which could apply to many other regenerative contexts, in which stem cells do not respond to the presence or absence of the specific tissue to be regenerated. How regeneration occurs following removal of specific tissues is poorly understood (Figure 1A). To address this problem, we developed tissue-specific surgical manipulations to partially or fully resect one or both of the planarian eyes (Figures 1B–1G and S1A–S1C). In all cases the injured or absent eye returned, representing the regeneration of an entire organ following its specific removal (Figures 1B–1G). We therefore utilized these tissue-specific surgical strategies in combination with various large injuries to seek the mechanistic basis of tissue-specific regeneration. Previously, we found that head amputation leads to increased neoblast-derived eye progenitor numbers (eye progenitor amplification), facilitating eye regeneration (Figure 2A ) (Lapan and Reddien, 2011Lapan S.W. Reddien P.W. dlx and sp6-9 control optic cup regeneration in a prototypic eye.PLoS Genet. 2011; 7: e1002226Crossref PubMed Scopus (102) Google Scholar, Lapan and Reddien, 2012Lapan S.W. Reddien P.W. Transcriptome analysis of the planarian eye identifies ovo as a specific regulator of eye regeneration.Cell Rep. 2012; 2: 294-307Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). If eye progenitor amplification following decapitation involved neoblasts responding to eye absence, then eye removal alone should also induce eye progenitor amplification. We therefore assessed whether eye resection was sufficient to increase eye progenitor numbers above basal levels found in uninjured animals. As expected, 3 days after injury, eye progenitor numbers were increased in response to decapitation. Surprisingly, however, eye progenitor numbers were not increased after eye resection (Figures 2B and 2C), despite the fact that eyes regenerated following this injury (Figure 1E). We also quantified eye progenitors every day for 1 week following injury. This time window allows substantial regeneration, including of a functional head and eyes, with animals capable of feeding and negative phototaxis. Eye-resected animals did not show elevated progenitor numbers at any of the eight time points quantified, whereas decapitated animals exhibited elevated progenitor numbers from day 3 to day 7 (Figure 2D). Quantification with a semi-automated computer protocol yielded similar results (Figures S1D–S1H). ovo RNAi animals did not regenerate eyes following eye resection, indicating that the amplification of an ovo− progenitor population does not contribute to eye regeneration in this context (Figure S1I). We conclude that eye absence alone is not sufficient to induce eye progenitor amplification. Although eye resection did not increase eye progenitor numbers, a tissue-specific increase in eye progenitor incorporation could in principle drive regeneration in this context. For instance, eye progenitors might only survive and incorporate into eyes that are disproportionately small or absent. More generally, if neoblasts respond to eye absence in a tissue-specific manner, then an eye-specific increase in progenitor incorporation should occur following eye resection. To assess progenitor incorporation rate, we utilized bromodeoxyuridine (BrdU) to label neoblasts (Newmark and Sánchez Alvarado, 2000Newmark P. Sánchez Alvarado A. Bromodeoxyuridine specifically labels the regenerative stem cells of planarians.Dev. Biol. 2000; 220: 142-153Crossref PubMed Scopus (376) Google Scholar) and quantified the number of BrdU+/opsin+ PRNs 6 days later. Whereas decapitation resulted in an increased rate of new PRN formation from neoblasts, eye resection alone did not (Figures 3A and 3B ). To exclude the possibility that we failed to observe an increase in PRN incorporation following eye resection because of the specific timing of our experiment, we systematically varied the timing of BrdU delivery and animal fixation with respect to surgery in uninjured, eye-resected, and decapitated animals (Figure 3C). In most cases decapitated animals had significantly more BrdU+/opsin+ cells than did uninjured animals. Conversely, in most cases no difference between eye-resected animals and uninjured controls was observed. A modest increase in PRN incorporation was observed in eye-resected animals only for the day 0–6 and day 1–7 delivery-fixation intervals. To determine whether this effect was specifically a consequence of eye absence, we resected a similar amount of tissue from a region lateral to the eyes and used the day 1–7 delivery-fixation interval to assess PRN incorporation. Tissue resection lateral to the eye resulted in a similar increase in PRN incorporation (Figure 3D). These data suggest that this modest, transient increase in progenitor incorporation is a generic consequence of injury-induced proliferation, rather than eye absence. This is consistent with a global wave of mitosis previously described to occur in planarians following any small injury (Baguñà, 1976Baguñà J. Mitosis in the intact and regenerating planarian Dugesia mediterranea n.sp. II. Mitotic studies during regeneration, and a possible mechanism of blastema formation.J. Exp. Zool. 1976; 195: 65-80Crossref Scopus (83) Google Scholar, Wenemoser and Reddien, 2010Wenemoser D. Reddien P.W. Planarian regeneration involves distinct stem cell responses to wounds and tissue absence.Dev. Biol. 2010; 344: 979-991Crossref PubMed Scopus (223) Google Scholar). Tissue-specific regeneration also occurred in the case of single eye removal, enabling paired comparisons of regenerating and non-regenerating eyes within the same individuals (Figure 1F). Uninjured and regenerating eyes had similar incorporation rates regardless of the delivery-fixation interval (Figures 3E and S2). We also used perdurance of the neoblast protein SMEDWI-1 (Guo et al., 2006Guo T. Peters A.H. Newmark P.A. A Bruno-like gene is required for stem cell maintenance in planarians.Dev. Cell. 2006; 11: 159-169Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, Reddien et al., 2005Reddien P.W. Oviedo N.J. Jennings J.R. Jenkin J.C. Sánchez Alvarado A. SMEDWI-2 is a PIWI-like protein that regulates planarian stem cells.Science. 2005; 310: 1327-1330Crossref PubMed Scopus (459) Google Scholar, Scimone et al., 2010Scimone M.L. Meisel J. Reddien P.W. The Mi-2-like Smed-CHD4 gene is required for stem cell differentiation in the planarian Schmidtea mediterranea.Development. 2010; 137: 1231-1241Crossref PubMed Scopus (75) Google Scholar) as a marker of newly differentiated PRNs, providing a second direct readout of progenitor incorporation rate into the eye. Whereas animals regenerating from decapitation showed elevated numbers of SMEDWI-1+/opsin+ PRNs, animals regenerating from eye resection did not (Figures 3F and 3G). We conclude that tissue-specific eye regeneration, following eye resection, is accomplished in the absence of a tissue-specific neoblast response. How are the eyes specifically regenerated following eye resection if their absence is not sensed by neoblasts, and there is no specific alteration in their progenitor production or incorporation rates? For instance, in animals with only one resected eye, the intact eye and the regenerating eye have the same rate of progenitor incorporation (Figures 1F and 3E). Thus, how does growth occur only on the injured side? Because the size of a tissue remains constant when cell production and cell death are in equilibrium, alteration in either process can affect tissue size. Therefore, if the rate of eye progenitor incorporation remains constant following eye resection, then the rate of cell loss in regenerating eyes (defined as total cell loss events per eye per unit time) must be lower in the regenerating eye in order to facilitate net growth. To test this prediction, we sought to compare rates of cell loss in uninjured and regenerating eyes (Figure 4A). Animals underwent right eye resection, leaving left eyes uninjured. Right eyes were allowed to partially regenerate for 8 days. Animals were then irradiated with 6,000 rad, a procedure that specifically and rapidly eliminates neoblasts (Figure 4A) (Dubois, 1949Dubois F. Contribution á l ’ètude de la migration des cellules de règènèration chez les Planaires dulcicoles.Bull. Biol. Fr. Belg. 1949; 83: 213-283Google Scholar) and neoblast-derived eye progenitors (Lapan and Reddien, 2011Lapan S.W. Reddien P.W. dlx and sp6-9 control optic cup regeneration in a prototypic eye.PLoS Genet. 2011; 7: e1002226Crossref PubMed Scopus (102) Google Scholar), but that has no detectable effect on differentiated planarian tissues (Guo et al., 2006Guo T. Peters A.H. Newmark P.A. A Bruno-like gene is required for stem cell maintenance in planarians.Dev. Cell. 2006; 11: 159-169Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, Reddien et al., 2005Reddien P.W. Oviedo N.J. Jennings J.R. Jenkin J.C. Sánchez Alvarado A. SMEDWI-2 is a PIWI-like protein that regulates planarian stem cells.Science. 2005; 310: 1327-1330Crossref PubMed Scopus (459) Google Scholar, Wagner et al., 2011Wagner D.E. Wang I.E. Reddien P.W. Clonogenic neoblasts are pluripotent adult stem cells that underlie planarian regeneration.Science. 2011; 332: 811-816Crossref PubMed Scopus (440) Google Scholar, Wagner et al., 2012Wagner D.E. Ho J.J. Reddien P.W. Genetic regulators of a pluripotent adult stem cell system in planarians identified by RNAi and clonal analysis.Cell Stem Cell. 2012; 10: 299-311Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Because neoblasts are the only dividing planarian cells and the sole source of new differentiated tissue (Newmark and Sánchez Alvarado, 2000Newmark P. Sánchez Alvarado A. Bromodeoxyuridine specifically labels the regenerative stem cells of planarians.Dev. Biol. 2000; 220: 142-153Crossref PubMed Scopus (376) Google Scholar), subsequent alterations in the number of eye cells could be attributed to eye cell loss. We therefore predicted that the right eyes, which were regenerating at the time of irradiation, would decrease in size more slowly than the uninjured left eyes. To quantify eye size, we counted the total number of PRNs per eye (Figure S3A). As predicted, uninjured left eyes significantly decreased in size from day 3 to day 10 post irradiation (Figures 4B and 4C). Uninjured eyes also decreased in size following irradiation when the contralateral eye was not injured, indicating that this effect was not a consequence of contralateral eye absence (Figure S3B). In contrast to the uninjured left eyes, regenerating right eyes did not significantly decrease in size, indicating that less cell loss occurred in the regenerating eye during this interval (Figures 4B and 4C). Consistent with these observations, the intra-animal PRN number difference between uninjured and regenerating eyes was decreased from day 3 to day 10 post irradiation (Figure S3C). The ratio of PRNs in the regenerating to uninjured eye was increased over this time interval, also demonstrating proportionally less cell loss in the regenerating eye (Figure 4D). We also used fluorescence in situ hybridization (FISH) combined with whole-mount TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) (Pellettieri et al., 2010Pellettieri J. Fitzgerald P. Watanabe S. Mancuso J. Green D.R. Sánchez Alvarado A. Cell death and tissue remodeling in planarian regeneration.Dev. Biol. 2010; 338: 76-85Crossref PubMed Scopus (243) Google Scholar) to observe apoptotic cell death events in intact and regenerating PRNs (Figures 4E and S3D). Apoptosis accounts for a small fraction of the lifetime of a cell, making TUNEL+/opsin+ PRNs rare. We therefore analyzed >350 eyes that were uninjured or regenerating from eye resection. A greater proportion of uninjured eyes contained TUNEL+/opsin+ PRNs than did regenerating eyes (Figure 4F). Taken together, our data indicate that regenerating eyes specifically exhibit a decrease in the rate of cell death (cell death events per eye per unit time), facilitating net growth without a specific increase in eye progenitor incorporation. Based on these findings, we propose a simple, passive model for tissue-specific eye regeneration (Figure 5A), in which the rate of eye cell production by progenitors remains constant. Following eye resection, there are initially zero cells available for cell death, allowing any addition of new cells to result in net growth. In the following days, fewer cells are available for cell death than during homeostasis, with no old PRNs present. Net growth thus continues because the rate of cell death is less than the rate of incorporation, as a passive consequence of the emergent properties of a regenerating eye. As sufficient numbers of PRNs accumulate and age, the rate of cell death per eye once again matches the rate of incorporation events per eye, resulting in homeostatic eye size. This model allows tissue-specific eye regeneration to occur while not requiring neoblasts to specifically interpret or respond to the absence of the eye. Consistent with this passive model, the rate of eye degrowth following irradiation was similar to the rate of growth following eye resection, indicating that both incorporation and cell death occur at appreciable rates during homeostasis (Figure S4A). Furthermore, unlike the case for regenerating eyes described above, partially resected eyes (Figure 1G) decreased in size at a rate comparable with larger, uninjured eyes following irradiation (Figures S4B and S4C). This is consistent with cell age contributing to PRN death because unlike regenerating eyes, partially resected eyes are not exclusively composed of young cells. The result also indicates that an active size-sensing mechanism is unable to suppress death in partially resected eyes. Our passive model for tissue-specific eye regeneration also predicts that eyes regenerate following resection, but slowly. Indeed, eye-resected animals regenerated eyes more slowly than did decapitated animals, despite the fact that decapitated animals were significantly smaller than their eye-resected counterparts because of surgery and had to regenerate not only the eyes but also all other cell types of an entire head (Figures 5B, 5C, S5A, and S5B). Our data indicate that eye progenitor amplification is not a consequence of eye removal. We therefore sought to explore how large injuries induce eye progenitor amplification if eye absence is not regulating this process. Tail removal did not increase eye progenitor numbers in uninjured heads (Figure 6A ), indicating that the response does not simply occur after any wound removing a large amount of tissue. Anterior incisions made in the same location as decapitation, but that did not remove the head, also failed to significantly increase eye progenitors (Figure 6A), indicating that eye progenitor amplification requires anterior wounds that remove tissue. Injuries removing substantial tissue (such as amputation) differ from wounds that do not remove tissue (such as incisions) in multiple ways. Importantly, amputations but not incisions elicit a sustained increase in neoblast proliferation that is localized near the wound site (Wenemoser and Reddien, 2010Wenemoser D. Reddien P.W. Planarian regeneration involves distinct stem cell responses to wounds and tissue absence.Dev. Biol. 2010; 344: 979-991Crossref PubMed Scopus (223) Google Scholar). Accordingly, decapitation increased proliferation in the pre-pharyngeal region (assessed with phosphorylated histone H3 [H3P] immunofluorescence), whereas eye resection, tail amputation, and anterior incisions did not (Figure 6B). Specification of eye progenitors occurs in a spatially restricted manner within the head and pre-pharyngeal region (Lapan and Reddien, 2011Lapan S.W. Reddien P.W. dlx and sp6-9 control optic cup regeneration in a prototypic eye.PLoS Genet. 2011; 7: e1002226Crossref PubMed Scopus (102) Google Scholar, Lapan and Reddien, 2012Lapan S.W. Reddien P.W. Transcriptome analysis of the planarian eye identifies ovo as a specific regulator of eye regeneration.Cell Rep. 2012; 2: 294-307Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). We therefore hypothesized that eye progenitor amplification occurs as a consequence of injury-induced proliferation in the body position where eye progenitors are specified, rather than as a consequence of eye absence. To explore this possibility, we assessed neoblast proliferation and eye progenitor amplification in the pre-pharyngeal region following wounds that removed progressively increasing amounts of anterior tissue. Animals were left uninjured or underwent transverse amputation just anterior to the eyes, transverse amputation just posterior to the eyes, or full decapitation (Figure 6C). Neoblast proliferation in the pre-pharyngeal region increased proportionately with the amount of anterior tissue removed (Figure 6D) and eye progenitor amplification also occurred, closely paralleling the degree of neoblast proliferation (Figure 6E). Importantly, the difference in eye progenitor numbers between pre-eye and post-eye amputations was very small, despite the fact that one injury type left the eyes intact while the other completely removed them. The fact that eye progenitor numbers increased following amputation of the anterior head tip, an injury that did not remove eyes or eye progenitors, also demonstrates that eye absence is not required for increased eye progenitor production (Figures 6E and S6A). Amputated body fragments, such as tails, initially lack the region where eye progenitors are specified, yet they produce large numbers of eye progenitors de novo and regenerate eyes. Positional information is required for maintenance of the planarian adult body plan and proper regeneration (Reddien, 2011Reddien P.W. Constitutive gene expression and the specification of tissue identity in adult planarian biology.Trends Genet. 2011; 27: 277-285Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Regional expression gradients of patterning molecules (such as Wnt, BMP, and FGFRL/ndl) exist in planarian body wall muscle (Scimone et al., 2016Scimone M.L. Cote L.E. Rogers T. Reddien P.W. Two FGFRL-Wnt circuits organize the planarian anteroposterior axis.Elife. 2016; 5: e12845Crossref PubMed Scopus (70) Google Scholar, Witchley et al., 2013Witchley J.N. Mayer M. Wagner D.E. Owen J.H. Reddien P.W. Muscle cells provide instructions for planarian regeneration.Cell Rep. 2013; 4: 633-641Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar), and the pattern of expression of these molecules is restored early in the process of regeneration. In tails, anterior patterning molecules reappear by 48 hr post amputation (Figure 6F) (Gurley et al., 2010Gurley K.A. Elliott S.A. Simakov O. Schmidt H.A. Holstein T.W. Sánchez Alvarado A. Expression of secreted Wnt pathway components reveals unexpected complexity of the planarian amputation response.Dev. Biol. 2010; 347: 24-39Crossref PubMed Scopus (155) Google Scholar, Petersen and Reddien, 2009Petersen C.P. Reddien P.W. A wound-induced Wnt expression program controls planarian regeneration polarity.Proc. Natl. Acad. Sci. USA. 2009; 106: 17061-17066Crossref PubMed Scopus (174) Google Scholar), coinciding with increased neoblast proliferation (Figure 6H) (Wenemoser and Reddien, 2010Wenemoser D. Reddien P.W. Planarian regeneration involves distinct stem cell responses to wounds and tissue absence.Dev. Biol. 2010; 344: 979-991Crossref PubMed Scopus (223) Google Scholar) and the location of de novo eye progenitor amplification (Figure 6I). Therefore, similar to the case of decapitated animals, eye progenitor amplification in tail fragments involves significant tissue removal and induction of sustained neoblast proliferation in a region coinciding with the location of eye progenitor specification (the anterior-facing wound expressing head patterning molecules). We propose that it is not the absence of eyes promoting eye progenitor amplification in either case. We utilized additional injuries to further test predictions of the hypothesis that eye progen" @default.
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• W2594920429 title "Eye Absence Does Not Regulate Planarian Stem Cells during Eye Regeneration" @default.
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