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Elucidating the Way Back to a Younger State: Which Genes Are Involved in Reverse Development?

INTRODUCTION

The regeneration or rejuvenation of animal cells have always been an interesting topic and represent an actual field of challenge and debate due to the many potential applications in the medical field. Regeneration can possibly arise by transdifferentiation of existing cells or by stem cells (totipotent cells that can generate any differentiated cell). In both cases, the response occurs according to chemical, genetic, and physiological signals. These mechanisms can be activated to give rise to a whole array of new cell types (Brockes, 1998; Slack, 2003). A deeper understanding of the mechanisms underlying rejuvenation would provide a first step towards interpreting the biology of senesce and bringing new insight for future application on regenerative medicine.

Cnidarians are incredibly diverse animals exclusively found in aquatic and mostly marine environments. Jellyfish, corals, sea anemones, and hydras are among the most prominent representatives of this taxon. One of their typical features is the presence of cnidocytes, specialized cells that are used for prey capture and defense. Cnidarians have long been considered simple animals but they present a variety of complex life cycles and developmental patterns. In addition, they are the only known group of organisms with the potential to undergo reverse development (RD) (Schmich et al., 2007). Reverse development was first discovered in scyphozoans more than a century ago (Hadzi, 1909) and represents an unparalleled feature of cnidarians within the animal kingdom (Piraino et al., 2004). Since the discovery of this mechanism, several hydrozoan species have shown the potential to reverse their ontogenetic programs (Piraino et al., 2004).

Under normal conditions, their general life cycle is characterized by the alternation of a post-larval benthic polyp and an adult pelagic medusa (Figure 1). The sexually mature adult medusa releases gametes, which, upon fertilization, form short-lived lecithotrophic (non-feeding) planulae. The planulae settle on to a substrate and form larval hydroids. The hydroids grow asexually, usually forming colonies. Through a complex process that involves the entocodon (medusary nodule), hydroids produce and release medusae, completing the cycle (Boero & Bouillon, 1987; Boero et al., 1998; Boero et al., 2002). Interestingly, some hydrozoan species are also able to revert their life cycle. In these cases, the adult medusa goes back to the juvenile stage of polyp as an adaptive strategy to deal with environmental stress (Carlà et al., 2003; Piraino et al., 2004; Schmich et al., 2007).

To date, different cnidarian species have been identified as performing RD, such as Turritopsis nutricula, T. dohrnii, and Hydractinia carnea (Schmich et al., 2007; Piraino et al., 2004). Furthermore, species belonging to the Turritopsis genus are among the few known species with the ability to perform RD from a free-living medusa to a polyp state after becoming sexually mature (Bavestrello et al., 1992; Piraino et al., 1996). Through stereoscopy observation, Carlà and colleagues (2003) identified four stages during the life cycle of T. nutricula and categorized them as healthy medusa, unhealthy medusa, four-leaf clover and cyst. According to these authors, the healthy medusa has a bell-shaped umbrella with long tentacles and swims actively. The unhealthy medusa is not able to swim and maintains its tentacles in a retracted position, and the typical transparency of the normal healthy medusa is lost. The four-leafed stage is characterized by the absence of tentacles and the reduction of the sub-umbrella cavity, which shows a number of lobes and many degenerative processes. During the cyst stage the organism is spherically shaped, with a smooth surface; this cyst is able to attach to the substrate and rapidly give rise to a polyp stage. Although RD was identified in several species, most of them undergo some restrictions in expressing transdifferentiation at the adult stage. For instance, in Hydractinia carnea, the potential for RD is lost in older medusa stages (Schmich et al., 2007).

Reverse development (or cell transdifferentiation) is a process by which a mature somatic cell transforms into another mature somatic cell without undergoing an intermediate pluripotent state or progenitor cell type (Graf & Enver, 2009). Transdifferentiation also involves a change in commitment and gene expression of well-differentiated, non-cycling somatic cells to other cell types (Okada 1991). In some medusa species, transdifferentiation occurs in all cells, e.g. those of the manubrium, tentacular bulbs, radial canals, exumbrellar rim, marginal canal, subumbrellar rim, or even gonads (Piraino et al. 2004). Degenerative and apoptotic cellular morphological modifications are involved during the RD of T. nutricula. It has been shown that the gonads are retained throughout all stages, thus showing evidence that both young and mature medusa can undergo reversion (Carlà et al. 2003).

Transdifferentiation is a very interesting mechanism that can provide many insights for the development of tolls and products for regenerative medicine, such as treatments for heart diseases. Postnatal cardiomyocytes have little or non-regenerative capacity; although, endogenous cardiac fibroblasts are able to differentiate in beating cardiac cells replacing damaged cardiomyocytes. In a study performed by Ieda and colleagues (2010), a specific combination of three transcription factors was identified as being able to generate functional beating cardiomyocytes directly from mouse postnatal cardiac fibroblast. In addition, the induced cardiomyocytes were globally reprogrammed to a cardiomyocytes-like gene expression profile.

The main goal of this proposal is to investigate which signaling networks are involved in stage differentiation during hydrozoans life cycle, in order to identify and understand the mechanisms underlying RD. We will thus focus on two marine hydrozoans, Turritopsis dohrnii and Hydractinia carnea, which were previously compared under different chemical and physical conditions and showed a different potential for RD (Schmich et al., 2007).

We strongly believe that our results will pave the way for future studies aiming to clarify the mechanisms of senescence and rejuvenation.


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Figure 1. Models of some hydrozoan life cycles (removed from Piraino et al., 2004). (A) Hydra spp. has no medusa stage and no planula larva. Asexual budding of new polyps is the most frequent mode of reproduction. (B) Hydractinia echinata has a highly reduced medusa stage that remains attached to the polyp in the form of fixed gonophores. Fertilization leads to the formation of a planula larva, which will undergo metamorphosis to develop into a polyp colony. (C) The life cycle of Hydractinia (Podocoryna) carnea includes a swimming medusa stage and a planula larva. Artificial detachment of late medusa buds leads to the development of medusae that are complete but reduced in size. In contrast, artificially detached early medusa buds are capable of transformation back into polyps. Such reverse transformation is not usually achieved by late medusa buds or liberated medusae. (D) Turritopsis nutricula has a typical three-stage life cycle: planula, polyp, and medusa. However, medusae at all stages of development retain the potential for life-cycle reversal; even spent medusae do not die, but transform back spontaneously into new polyp colonies (Piraino et al., 2004).


REFERENCES

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Hector Aguilar
Victor Borda
Maria Breitman
Kuhan Chandru
Juliana David
Vitoria Santos
Francesca Scolari
Larissa Silva

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