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Axis formation in annual killifish: Nodal coordinates morphogenesis in absence of Huluwa prepatterning

Philip B. Abitua, Deniz C. Aksel, Alexander F. Schier

Preprint posted on April 17, 2021 https://www.biorxiv.org/content/10.1101/2021.04.16.440199v1

Self-organization and spontaneous symmetry-breaking allow the annual killifish embryos to resume normal development after the “summer break”.

Selected by Girish Kale

Background:

How the entire organism is formed, starting from a single cell, has fascinated researchers for many decades, long before the discovery of DNA. Naturally, a lot of work has gone into investigating the embryonic development of various animals. So, when the current understanding doesn’t explain the embryonic development of a species, that’s a head scratcher.

The canonical developmental programs crucially rely on maternal information to guide the early development of the embryo. Depending on the species, this information is necessary to orient the head-tail, front-back, and left-right coordinates of the embryo, and to specify cell identities. In this way, the embryonic development of annual killifish is highly unusual, as it occurs in the absence of conserved maternal information. Moreover, the embryo goes through a phase of active dispersion of cells, thus homogenising any asymmetries, followed by a stasis period that can last for months. At this stage, the cells are also in a pluripotent state, as the authors couldn’t detect any markers of early differentiation. This manuscript addresses how the symmetry is broken before the developmental program is restarted.

Key findings:

In this preprint, the authors find a special role for the morphogen Nodal, which is known to specify the precursor tissues for the future gut (endoderm), and other internal organs (mesoderm), like the heart. If maternal information in present, Nodal has only a secondary role to specify the precursor tissues. But in the absence of maternal information, as in the annual killifish Nothobranchius furzeri, Nodal is tasked with additional duties. The authors compare the development of the annual killifish to the zebrafish (Danio rerio), where Nodal signalling amplifies the maternal information that has already localised mesoderm and endoderm in the dorsal side of the embryo. In the absence of the front-back/ventral-dorsal orientation, the annual killifish embryos rely on Nodal signalling, which is now triggered by a sporadic aggregation of cells, to specify the dorsal side at the location of the cell aggregate. The authors also demonstrate similarities with zebrafish for the subsequent developmental stages, further arguing that the embryo resumes canonical development after the initial establishment of the embryo axes.

In addition, the authors identify the key evolutionary changes associated with the emergence of this new developmental program. Canonical development, as observed in zebrafish, begins with several rounds of cell divisions that form a cell aggregate, called the blastoderm. In this aggregate, Huluwa stabilises βCatenin in order to specify the dorsal side. So why doesn’t Huluwa perform the same task in annual killifish? The authors find that the Huluwa gene in annual killifish is non-functional, and has turned into a “pseudogene” due to a single point mutation in the Huluwa coding region. They demonstrate the non-functionality of this Huluwa variant by introducing it in the zebrafish at early stages. If native Huluwa is introduced at early stages in zebrafish embryos, then the embryos show developmental defects due to an excess of Huluwa and hyper-stabilisation of βCatenin. Introduction of the killifish version of Huluwa in early stages during the development of zebrafish embryos has no adverse effects, demonstrating its non- functionality. With these results, the authors conclude that a loss of Huluwa function, and the additional developmental burdens on Nodal signalling, are sufficient to explain the evolutionary changes in the early developmental program in the annual killifish.

Importance of the findings:

How do these evolutionary changes benefit the fish? The authors argue that the stringent conditions during the life-cycle of killifish might be the answer. At the end of mating season, killifish lay eggs in shallow water, which is going to evaporate over the summer. So, the embryos need to survive these conditions and, when the environment is favourable, start the development again. Canonical developmental programs are not adapted for such long periods of stasis as they rely on morphogen gradients, which would be flattened due to diffusion over extended periods of time, and/or predetermined cell identities, which might be lost if a fraction of cells die during the extreme environment during the stasis period. A cell re-aggregation and de novo establishment of cell identities circumvent both of these problems, and has arguably allowed annual killifish to occupy habitats that would be inaccessible to other fishes.

Future directions and questions:

The ideas described in the preprint are reminiscent of organoids, where research focuses on developing strategies to produce artificial organs and tissues, starting from pluripotent stem-cells. It is still puzzling how organoid cell-aggregates break symmetry and self-organise to form layers of differentiated cells. What’s even more challenging, is to experimentally control the cell fates in the organoids, such that a particular tissue can be formed and not the other. It is quite clear that nature has solved this puzzle, at least as far as annual killifish development is concerned. What can we learn from annual killifish development that would help organoid research? (see also author response #1)

This preprint makes one think about the mechanisms that help an organism survive through extreme environmental conditions. The general nature of the principles we learn here, might also render them applicable in other contexts e.g., survival after vacuum desiccation or cryopreservation. Thinking on similar lines, hibernation is another example where life cycle is paused to survive extreme environment, though in adults. Is it possible to synthesise a conceptual framework to think about how organisms pause their life cycle, and then resume it when environment is favourable? (see also author response #2)

One thing is clear; it would be extremely interesting to identify more organisms, like the annual killifish, that pause their embryonic development, after which a de novo initiation of fate specification re-establishes cell-identities and the life cycle is resumed.

 

Posted on: 8th June 2021 , updated on: 10th June 2021

doi: https://doi.org/10.1242/prelights.29520

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Author's response

Philip B. Abitua shared

1) At its core, organoid research is an engineering problem. In the case of gastruloids, scientists are trying to understand how you take an aggregation of embryonic stem cells and induce them into tissue with spatially organized germ layers, essentially making embryos from scratch. This amazing feat would not be possible without the wealth of information from classical developmental biology, which instead tries to understand embryos by deconstructing them though reverse engineering. The problem is, most of our knowledge of developmental biology comes from a handful of model organisms. By studying annual killifish that naturally self-organize, we can decipher nature’s solution and use those design principles to make organoid engineering more exact. The crazy thing is, it could be a radically different solution than the one used by mammals, but it could still work to engineer human embryonic stem cells.

2) Some diapausing insects are more cold tolerant and desiccation resistant compared to their non-diapausing counterparts. These tolerances to extreme environments may have been stress responses that were co-opted into diapause pathways. For example, heat shock proteins are upregulated during diapause in flesh flies and may function as a backup mechanism to halt development since they promote cell cycle arrest. Annual killifish are also known to survive desiccating conditions. It will be interesting to further explore how extreme environmental tolerances evolved and in which sequence relative to the evolution of diapause.

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