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Wnt/Notum Spatial Feedback Inhibition Controls Neoblast Differentiation to Regulate Reversible Growth of the Planarian Brain Eric M

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Wnt/Notum Spatial Feedback Inhibition Controls Neoblast Differentiation to Regulate Reversible Growth of the Planarian Brain Eric M © 2015. Published by The Company of Biologists Ltd | Development (2015) 142, 4217-4229 doi:10.1242/dev.123612 STEM CELLS AND REGENERATION RESEARCH ARTICLE Wnt/Notum spatial feedback inhibition controls neoblast differentiation to regulate reversible growth of the planarian brain Eric M. Hill1 and Christian P. Petersen1,2,* ABSTRACT 2013; Wills et al., 2008a,b); hence, they represent model systems Mechanisms determining final organ size are poorly understood. well suited for investigating the developmental mechanisms that Animals undergoing regeneration or ongoing adult growth are likely to underlie the extent of growth and attainment of size (Baguñà and require sustained and robust mechanisms to achieve and maintain Romero, 1981; Oviedo et al., 2003; Wada et al., 2013). appropriate sizes. Planarians, well known for their ability to undergo Planarians are flatworms that continue to undergo significant whole-body regeneration using pluripotent adult stem cells of the tissue turnover throughout adulthood and exhibit an extreme neoblast population, can reversibly scale body size over an order of capacity for growth control that allows reversible alteration of magnitude by controlling cell number. Using quantitative analysis, we body and organ size over an order of magnitude through the showed that after injury planarians perfectly restored brain:body regulation of cell number. Nutrient uptake leads to an increase in ‘ ’ proportion by increasing brain cell number through epimorphosis body size, whereas prolonged starvation results in degrowth ,a or decreasing brain cell number through tissue remodeling reduction of body size and cell number without an alteration in (morphallaxis), as appropriate. We identified a pathway controlling a relative tissue proportions or function (Baguñà and Romero, 1981; brain size set-point that involves feedback inhibition between wnt11- Morgan, 1898; Oviedo et al., 2003; Romero and Baguñà, 1991; 6/wntA/wnt4a and notum, encoding conserved antagonistic signaling Takeda et al., 2009). Additionally, planarians exhibit robustness in factors expressed at opposite brain poles. wnt11-6/wntA/wnt4a growth control through the process of regeneration. Planarians do undergoes feedback inhibition through canonical Wnt signaling not appreciably increase in size during regeneration, so small but is likely to regulate brain size in a non-canonical pathway amputated tissue fragments ultimately become small but well- independently of beta-catenin-1 and APC. Wnt/Notum signaling formed individuals, in which overt body proportionality appears tunes numbers of differentiated brain cells in regenerative growth and broadly restored (Morgan, 1898). Planarians accomplish tissue remodeling by influencing the abundance of brain progenitors regeneration both by the production of missing structures in a descended from pluripotent stem cells, as opposed to regulating cell regeneration blastema (termed epimorphosis) and through death. These results suggest that the attainment of final organ size remodeling of pre-existing tissues [originally termed morphallaxis might be accomplished by achieving a balance of positional signaling (Morgan, 1898)]. The term morphallaxis has also been used to inputs that regulate the rates of tissue production. describe putative regeneration mechanisms that might occur independently of cell proliferation (Morgan, 1901); therefore, for KEY WORDS: Wnt signaling, Notum, Organ size, Planaria, clarity we will describe the process of injury-induced alterations to Regeneration, Tissue remodeling pre-existing tissues as ‘tissue remodeling’ (Forsthoefel et al., 2011; Oviedo et al., 2003). Planarians reproduce asexually by fission, so INTRODUCTION they are a suitable model to study the mechanisms of natural Most animal species possess stereotyped body forms, in which proportion regulation and organ sizing through control of cell organs and appendages grow to defined proportions with respect to number (Oviedo et al., 2003). total body size. Mutations that alter organ proportion can underlie The relationships between epimorphosis and tissue remodeling evolutionary changes (Abzhanov et al., 2004; Jones et al., 2012) and are not fully understood, but several cellular events and molecular result in human developmental disorders, such as microcephaly pathways have been identified as contributing to each of these (Mochida and Walsh, 2001). Many molecular pathways have been processes. Growth from feeding or epimorphic regeneration described as contributing to growth regulation (Conlon and Raff, depends on parenchymal cells termed neoblasts that are the only 1999; Lander, 2011; Schwank and Basler, 2010; Tumaneng et al., proliferating cells in adult planarians (Baguñà, 1976; Newmark and 2012), primarily through genetic studies of species that cease or Sánchez Alvarado, 2000; Reddien et al., 2005b). Neoblasts are a largely dampen growth at the end of embryogenesis, but despite heterogeneous population containing both adult pluripotent stem considerable interest, the developmental mechanisms explaining cells (Wagner et al., 2011) and more lineage-restricted dividing cells size attainment largely remain a mystery. By contrast, species that (Adler et al., 2014; Cowles et al., 2013; Currie and Pearson, 2013; undergo regeneration and ongoing growth throughout adulthood Forsthoefel et al., 2012; Lapan and Reddien, 2012; Marz et al., must possess robust mechanisms to control animal form and 2013; Scimone et al., 2014a,b, 2011; van Wolfswinkel et al., 2014; proportion actively (Elliott and Sánchez Alvarado, 2013; Rink, Vásquez-Doorman and Petersen, 2014; Vogg et al., 2014; Wenemoser et al., 2012). Tissue removal results in proliferative 1Department of Molecular Biosciences, Northwestern University, Evanston, activation of neoblasts thought to be necessary for production of IL 60208, USA. 2Robert Lurie Comprehensive Cancer Center, Northwestern missing tissue types within the regeneration blastema. By contrast, University, Evanston, IL 60208, USA. the cellular basis for regenerative tissue remodeling is less well *Author for correspondence ([email protected]) understood but has been proposed to involve a wave of systemic injury-induced cell death proportional to the extent of tissue Received 23 February 2015; Accepted 27 October 2015 removed by injury (Pellettieri et al., 2010). Within the intestine, DEVELOPMENT 4217 STEM CELLS AND REGENERATION Development (2015) 142, 4217-4229 doi:10.1242/dev.123612 regeneration involves both substantial differentiation of new cells numbers in decapitated animals forming a new brain through and incorporation of pre-existing cells, suggesting a complexity of epimorphosis (Fig. 1D, dotted lines; Fig. 1E, lower) or amputated tissue additions and alterations during regeneration (Forsthoefel head fragments undergoing brain remodeling (Fig. 1D, solid lines; et al., 2011). As planarians can perform tissue remodeling and Fig. 1E, upper). In order to allow evaluation of regenerative progress blastema formation through periods of starvation, it is possible that with respect to the complete body plan and across replicates of regulated autophagy could contribute to these processes (González- varying sizes, neural cell numbers were normalized to the total Estévez, 2009; González-Estévez et al., 2007). Perturbation of fragment length to give a value for brain:body proportion at each several molecular processes can influence body and organ size in time in regeneration (Fig. 1D). Relative brain size during planarians, including bioelectric signaling (Beane et al., 2012), FGF regeneration was compared with values interpolated from a power signaling (Cebrià et al., 2002a), JNK signaling (Almuedo-Castillo law regression analysis of brain cell number versus body length in et al., 2014), TORC1 signaling (González-Estévez et al., 2012b; uninjured animals to determine when appropriate organ size was Peiris et al., 2012; Tu et al., 2012) and insulin-like peptide signaling achieved (Fig. 1D, dashed black lines). In animals remodeling a pre- (Miller and Newmark, 2012). However, there is still a limited existing organ, brain:body proportion decreased rapidly during the understanding of the developmental and molecular events that 72 h following decapitation and continued to decrease until underlie the attainment and maintenance of appropriate organ size stabilizing around day 9. In epimorphic growth, cintillo+ and gad+ in planarians. neurons emerged around day 3, coincident with appearance of the We investigated the planarian brain as a model for regenerative brain primordia (Cebrià, 2007), and brain:body proportion organ size control, because it undergoes prominent and easily continued to increase until stabilizing by day 9. Throughout either identifiable changes in cell number (Oviedo et al., 2003). Here, we regeneration scenario, brains had a constant ratio of neuronal cell show that planarians completely restore appropriate brain:body numbers to brain length (Fig. S1F), indicating that proper scale proportions through either epimorphic growth or tissue remodeling. within the brain is established early and maintained through periods We find that the secreted Wnt inhibitor notum (Petersen and of organ size change (Takeda et al., 2009), whereas the proportion Reddien, 2011) is expressed in anterior brain neurons and promotes of the organ with respect to the body is subject to regulation. brain size in regeneration, remodeling and homeostasis. notum Although remodeling and epimorphosis ultimately achieved
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