Abstract
Mechanisms that enable injury responses to prompt regenerative outgrowth are not well understood. Planarians can regenerate essentially any tissue removed by wounding, even after decapitation, due to robust regulation of adult pluripotent stem cells of the neoblast population. Formation of pole signaling centers involving Wnt inhibitors or Wnt ligands promotes head or tail regeneration, respectively, and this process requires the use of neoblasts early after injury. We used expression profiling of purified neoblasts to identify factors needed for anterior pole formation. Using this approach, we identified zic-1, a Zic-family transcription factor, as transcriptionally activated in a subpopulation of neoblasts near wound sites early in head regeneration. As head regeneration proceeds, the Wnt inhibitor notum becomes expressed in the newly forming anterior pole in zic-1-expressing cells descended from neoblasts. Inhibition of zic-1 by RNAi resulted in a failure to express notum at the anterior pole and to regenerate a head, but did not affect tail regeneration. Both injury and canonical Wnt signaling inhibition are required for zic-1 expression, and double-RNAi experiments suggest zic-1 inhibits Wnt signaling to allow head regeneration. Analysis of neoblast fate determinants revealed that zic-1 controls specification of notum-expressing cells from foxD-expressing neoblasts to form the anterior pole, which organizes subsequent outgrowth. Specialized differentiation programs may in general underlie injury-dependent formation of tissue organizing centers used for regenerative outgrowth.
Highlights
Regeneration is widespread in animals but still poorly understood
We identify the zic-1 gene as activated in planarian stem cells by injury and needed for head regeneration after decapitation
Identification of zic-1 as induced in neoblasts early in head regeneration To identify genes involved in putative stem cell-dependent patterning processes, we first examined neoblast requirements for injury-induced expression of notum, a Wnt inhibitor required for head regeneration [14]
Summary
Regeneration is widespread in animals but still poorly understood. In animals with this ability, injury responses and positional cues likely interact to signal the production of missing structures. Rather than the presence or absence of a single regenerative cell type, patterning systems that directly or indirectly control such cells may instead be the critical determinate for regenerative abilities. Injuries can alter tissue variously, so regenerating animals must have robust cell signaling mechanisms that enable appropriate restoration of structures damaged or lost by wounding. An important unresolved issue in understanding regeneration mechanisms is whether stem cells function only in production of differentiated cell types that comprise fully regenerated structures, or whether they could have additional functions in directing outgrowth by controlling tissue patterning
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