Abstract
A longstanding challenge in regeneration biology is to understand the role of developmental mechanisms in restoring lost or damaged tissues and organs. As these body structures were built during embryogenesis, it is not surprising that a number of developmental mechanisms are also active during regeneration. However, it remains unclear whether developmental mechanisms act similarly or differently during regeneration as compared to development. Since regeneration is studied in the context of mature, differentiated tissues, it is difficult to evaluate comparative studies with developmental processes due to the latter’s highly proliferative environment. We have taken a more direct approach to study regeneration in a developmental context (regrowth). Xenopus laevis, the African clawed frog, is a well-established model for both embryology and regeneration studies, especially for the eye. Xenopus eye development is well-defined. Xenopus is also an established model for retinal and lens regeneration studies. Previously, we demonstrated that Xenopus tailbud embryo can successfully regrow a functional eye that is morphologically indistinguishable from an age-matched control eye. In this study, we assessed the temporal regulation of retinal differentiation and patterning restoration during eye regrowth. Our findings showed that during regrowth, cellular patterning and retinal layer formation was delayed by approximately 1 day but was restored by 3 days when compared to eye development. An assessment of the differentiation of ganglion cells, photoreceptor cells, and Müller glia indicated that the retinal birth order generated during regrowth was consistent with that observed for eye development. Thus, retina differentiation and patterning during regrowth is similar to endogenous eye development. We used this eye regrowth model to assess the role of known mechanisms in development versus regrowth. Loss-of-function studies showed that Pax6 was required for both eye development and regrowth whereas apoptosis was only required for regrowth. Together, these results revealed that the mechanisms required for both development and regrowth can be distinguished from regrowth-specific ones. Our study highlights this developmental model of eye regrowth as a robust platform to systematically and efficiently define the molecular mechanisms that are required for regeneration versus development.
Highlights
Many animals have the ability to undergo regeneration, the successful restoration of tissues and organs after injury, but some animals lack this ability
To better understand eye regrowth and assess this process as compared to normal eye development, we examined the temporal regulation of eye formation during regrowth at three successive 24-h timepoints
The ciliary margin zone (CMZ) is located at the periphery of the retina and produces all retinal cell types for eye growth post-embryonically (Hollyfield, 1971)
Summary
Many animals have the ability to undergo regeneration, the successful restoration of tissues and organs after injury, but some animals lack this ability. Even though there is considerable knowledge regarding the cellular and molecular pathways that regulate regeneration, the basic question of why the same tissues and organs from diverse (or even closely related) species often respond differently to injury and damage remains largely unanswered. To address this question, an area of focus has been to understand the role of developmental mechanisms in regeneration. A second challenge in understanding the role of developmental mechanisms in regeneration is that existing models largely seek to examine regeneration in adult or mature differentiated tissues. It remains difficult to pinpoint the developmental mechanisms that can be successfully manipulated for inducing adult regeneration
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