In preprints: new spiralian model system unlocks potential for understanding eye evolution and regeneration

The details of how specific genetic programs control the development of a particular structure, such as an animal eye, remain a mystery. Across species separated by millions of years of evolution, similar genes and regulatory networks are involved in eye development, but extensive evolutionary and genetic evidence tells us that animal eyes have evolved multiple times independently. Furthermore, although similar genes regulate eye development across animals, depending on the eye type, distinct members of the gene family are involved, network relationships change and genes important for one eye type are not present in another. Extensive study in vertebrate and fly models has, in each case, revealed important gene-to-phenotype relationships leading to very different eye types (Vopalensky and Kozmik, 2009). For example, the Pax6-Six-Dach-Eya retinal determination gene network (RDGN) is required for both fly and vertebrate eyes (Silver and Rebay, 2005). However, distinct family members of the sine oculis gene family, Six1/2 (so) and Six3/6 (Optix) have swapped important roles in RDGN regulation between fruit flies and vertebrates (Kumar, 2009). With only a sample size of two, it is difficult to reconcile how differences in similar gene networks arose and why they are present. To better understand the development and evolution of animal eyes, more genetically tractable representatives from a diversity of eye types must be studied. Until recently it has been a challenge to establish evolutionarily diverse models for understanding how genes relate to eye type. With access to sequencing and genome editing, new models can now be used to compare changes in gene networks and their specific outcomes in eye development.

A second mystery in biology remains: why humans cannot regenerate most tissue types, especially complex structures like the eye, whereas other animals can? This gap in our understanding stems from a dearth of regenerative models that can (1) also be compared with developmental programs of organogenesis within the same species, and (2) regenerate complex sensory structures. Compared with many animals, humans are particularly bad at regenerating most tissue types once they are damaged or lost. In the context of the eye, genetic mutations inducing photoreceptor cell death (and our lack of ability to regenerate these cells) lead to major causes of blindness such as macular degeneration (Sancho-Pelluz et al., 2008). This makes models that can regenerate complex sensory structures and also compare this process with developmental processes valuable for human health outcomes. Most developmental models such as fly, mouse or nematode, are also poor at regenerating complex structures. Zebrafish can regenerate some cells in the retina, but not the entire eye bulb. Models of whole-body regeneration such as flatworms and Hydra often exhibit simple structures, with limited numbers of tissues or cell types. Additional models that can regenerate the patterning for complex three-dimensional structures made of multiple tissue types could help unlock specific genetic programs for therapeutic uses.

Accorsi et al. (2024 preprint) have established a functional genetic model for eye development and regeneration in the golden apple snail, Pomacea canaliculata. Through morphology, histology and transcriptomics the authors establish the convergently evolved camera-type eye of the snail as a model complex structure. To address functional genetic questions during development, the authors have implemented a protocol for husbandry and CRISPR/Cas9-mediated gene editing of early embryos. Importantly they also show how this complex eye displays robust regeneration in the adult animal. Together, these features make the snail a powerful new model to test gene-to-phenotype relationships and evolution of complex structures like animal eyes. To test the proof of concept of this genetic model, the authors also knock out a Pax6-like gene, which has a highly conserved role during eye development in both vertebrates and flies. The expression of this gene is consistent with a role for eye development similar to other models, and its knockout leads to eyeless adults, a hallmark of Pax6 knockouts in flies and vertebrates.

With these results, the authors have established a powerful new model to understand the origins of the link between Pax6-mediated gene networks and eye development, as well as to understand the genetic programming required to regenerate complex structures such as eyes. Previous models for eye development and evolution come from two distantly related groups of bilaterally symmetric animals, flies and vertebrates. This narrow sampling of animal eye types has limited our understanding of eye evolution and therefore the gene-to-phenotype relationships that are important in development. The snail offers not only a genetically tractable eye model, but this eye is independently evolved in the third major group of bilaterally symmetric animals, the Spiralia (mollusks). Furthermore, none of the major animal models with complex eyes is particularly good at regeneration, limiting the questions we can ask about regeneration of eyes. Beyond eye regeneration, the use of the snail model can be extended to study regulation of other sensory organs or complex structures and provide comparisons between development and regeneration. To understand the rules of gene network regulation and phenotype, novel lineages and repeated examples are required. To understand regeneration, the process must be compared with embryonic development. In the case of the golden apple snail and this new study, both goals are accomplished, making this a powerful new model.