Elsevier

Current Opinion in Cell Biology

Volume 73, December 2021, Pages 19-25
Current Opinion in Cell Biology

Principles of regeneration revealed by the planarian eye

https://doi.org/10.1016/j.ceb.2021.05.001Get rights and content

Abstract

One approach to elucidating the principles of regeneration is to investigate mechanisms that regenerate a target organ. Planarian eyes are discrete, visible structures that are dispensable for viability, making them powerful for studying the logic of regeneration. Fate specification in eye regeneration occurs in stem cells (neoblasts), generating eye progenitors. Eye progenitor production is not responsive to the presence or absence of the eye, with regeneration explained by constant progenitor production in the appropriate positional environment. Eye progenitors display coarse spatial specification. A combination of eye-extrinsic cues and self-organization with differentiated eye cells dictate where migratory eye progenitors target. Finally, guidepost-like cells influence regenerating axons to facilitate the restoration of eye circuitry. These findings from the eye as a case study present a model that explains how regeneration can occur.

Section snippets

The planarian eye as a target for study of regeneration principles

A characteristic feature of many planarian species is their crossed-eye appearance (Figure 1a). Similar to all planarian tissues, the eyes regenerate robustly [1]. Planarian eyes are simple eyes that mediate negative phototaxis and are comprised of two major cell types: photoreceptor neurons and pigmented optic cup cells (Figure 1a) [2]. Photoreceptor neurons extend rhabdomeric process into the optic cup, where an R-opsin signaling cascade detects light [3, 4, 5, 6]. Photoreceptor neurons can

Regenerative fate specification occurs in stem cells

Planarian stem cells are called neoblasts. Transplantation experiments demonstrate that at least some neoblasts are pluripotent, being capable of making all differentiated cell types of the adult animal [11,12]. Neoblasts share many attributes: morphology (large nucleus and relatively simple cytoplasm), expression of germ cell–related genes, and mesenchymal localization surrounding organ systems [13,14]. By contrast, at the molecular and functional levels, the neoblasts are highly heterogeneous.

Fate specification is spatially coarse

Eye-specialized neoblasts are generated constitutively at a low rate in uninjured animals, where they are involved in tissue turnover (Figure 1b) [6]. The pattern of fate specification is very broad compared with the precise and discrete location of the eyes—from eyes to near the pharynx (Figure 1b) [6,19,20]. During head regeneration, eye progenitors are specified near the wound and migrate in two trails to their location of differentiation in the blastema (Figure 1b) [15]. The broad and

Progenitor production without target tissue surveillance: target-blind regeneration and the bystander effect

How does a regenerative system bring about the specific return of the tissue type that is missing? Such tissue-specific regeneration has been hypothesized to involve feedback signaling that informs a progenitor pool about the absence of a given tissue [21]. By contrast, evidence from the planarian eye suggests that it can regenerate without such surveillance (Figure 2) [19]. Because the eye is visible and discrete, it can be specifically removed entirely or partially. After eye-specific

Progenitor targeting is dictated by extrinsic cues and self-organization

Because eye progenitor specification is spatially coarse, these cells must migrate to precise locations, transition from a stem cell state toward differentiation, and interact with their target tissue to become functionally incorporated into it. Two major forces act on eye progenitors to determine where they migrate and differentiate: eye-external spatial cues and self-organization of eye progenitors into an existing eye (Figure 3a) [20,36].

A variety of experiments revealed how migratory cues

Muscle guidepost-like cells facilitate regeneration of functional neuronal circuits

In any organism that can regenerate missing neurons, some mechanism(s) must exist to facilitate the rewiring of neural projections for the functional return of neural circuits. The findings described previously suggest mechanisms that can bring about the return and maintenance of planarian eyes after injury. But how do regenerated eyes regain their function? In animal development, a variety of transient guidance mechanisms help axon projections assemble into proper circuitry. Included in these

Molecular genetics of regeneration and the planarian eye

This article largely focuses on the cellular principles of regeneration uncovered from studying the planarian eye. However, a host of molecular insights into patterning, cell fate specification, differentiation, and cell migratory targeting have also been uncovered from studies of the planarian eye. Because it is visible, some patterning phenotypes with important implications for understanding axis formation were identified by the presence of ectopic eyes (Figure 3b). For the AP axis, anterior

Conclusions

Studies of eye regeneration suggest multiple key principles can combine to promote regeneration. These principles include spatially coarse fate specification within the stem cells that form a blastema, regeneration in the absence of surveillance of tissue presence (target-blind regeneration) from the combination of positional information and constant progenitor fate specification, and regulation of progenitor targeting by the combined action of migratory cues and self-organization with the

Conflict of interest statement

Nothing declared.

Acknowledgements

The author would like to thank prior and current laboratory members who have been pioneers in the utilization of the planarian eye for the study of regeneration. Particular thanks go to Sylvain Lapan, Sam LoCascio, Deniz Atabay, and Lucila Scimone for their seminal contributions to the principles discussed here. Sylvain commented on parallels to the C. elegans vulva. Additional thanks to prior laboratory members whose work also contributed to understanding the molecular genetics of eye

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