These divergent functions presumably relate to the fact that FoxA proteins are so-called pioneer factors. Pioneer factors bind to DNA at specific sites, opening up the chromatin structure in many different contexts Zaret and Carroll, This means that they can function in combination with different transcription factors in different tissues.
As a pioneer factor, FoxA may have played a fundamental evolutionary role in coordinating the formation of the structures needed to ingest and process food in multicellular organisms, and has then retained and expanded that role throughout evolution.
Planarian FoxA is expressed in the developing and the mature pharynx, and also in scattered neoblast cells around the pharynx that cluster at the site of amputation. In the absence of FoxA, neoblasts are still present, but they fail to migrate to the amputation site and initiate regeneration, and instead appear to be misdirected to other sites. So is FoxA primarily required for correct cell migration or for correct organ specification?
It will be very interesting to explore the direct targets of FoxA in planarians to see if it has a similar master regulatory function. Alternatively, it has been proposed that the evolutionarily conserved function of FoxA lies in regulating particular types of cell migration and rearrangement during development, rather than primarily in specifying cell fate de-Leon, Since cell behaviour and cell fate are closely intertwined, it is hard to separate these functions.
However, a more detailed comparison of the targets of FoxA at different stages of planarian regeneration with the corresponding targets in other species could reveal the fundamental roles of this important transcription factor.
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Article citation count generated by polling the highest count across the following sources: Crossref , PubMed Central , Scopus. Planarian flatworms regenerate every organ after amputation. Adult pluripotent stem cells drive this ability, but how injury activates and directs stem cells into the appropriate lineages is unclear. Here we describe a single-organ regeneration assay in which ejection of the planarian pharynx is selectively induced by brief exposure of animals to sodium azide.
To identify genes required for pharynx regeneration, we performed an RNAi screen of genes upregulated after amputation, using successful feeding as a proxy for regeneration. We found that knockdown of 20 genes caused a wide range of regeneration phenotypes and that RNAi of the forkhead transcription factor FoxA , which is expressed in a subpopulation of stem cells, specifically inhibited regrowth of the pharynx.
Selective amputation of the pharynx therefore permits the identification of genes required for organ-specific regeneration and suggests an ancient function for FoxA-dependent transcriptional programs in driving regeneration. Learning more about the genes that allow flatworms to regenerate organs and tissue after amputation.
When the animal is not amputated, the stem cells residing in the protected region do not mobilize to repopulate the irradiated tissues Figure 4a. However, if the partially irradiated animal is then decapitated, a marked mobilization of neoblasts towards the wound site becomes readily apparent Figure 4b,c [ 22 ]. The fact that neoblasts do not appear to migrate in the absence of amputation, while at the same time continuing to effect tissue homeostasis [ 21 ], indicates that different mechanisms for restorative versus injury induced regeneration are likely to exist.
In vivo migration of stem cells in planarians. Arrow points to neoblasts at or near the site of amputation. Neoblasts are in green Smed-piwi-1 and post-mitotic progeny in magenta Prog Modified from [ 22 ]. We demonstrated the efficiency and specificity of this method in planarians by targeting and measuring the protein products of the myosin and tubulin genes Figure 5a , which appeared in press a year later [ 23 ].
Presently, RNAi is the principal methodology being used by the planarian community to functionally interrogate genes and their functions in this organism. This method has allowed investigators to uncover remarkable phenotypes in RNAi-based screens [ 24 ] and signaling pathway perturbations Figure 5b [ 13 , 25 ]. Regeneration remains one of the last untamed frontiers of developmental biology. It is amongst the oldest biological problems known to humankind, dating back to antiquity in many cultures and, perplexingly, still awaiting a satisfactory mechanistic explanation.
It is my firm belief that the time to plumb the molecular depths of regeneration is now. Tremendous strides have been made in the study of regeneration in Hydra, planarians, zebrafish, newts, and salamanders.
Hence, a critical mass of knowledge is accruing that would permit a systematic interspecies comparison of regenerative capacities across very distant and diverse phyla. Equally important, a systematic and formal exploration of how the mechanisms of regeneration compare to embryogenesis can now begin in earnest.
Such a comparison would help address the long-standing question of whether regeneration is simply a recapitulation of development or made possible by independent mechanistic innovations.
In the case of planarians, are their embryonic stem cells functionally different from neoblasts? When during embryogenesis are neoblasts specified? To what extent are embryonic axes formation and organogenesis mechanisms similar or dissimilar between planarian embryogenesis and regeneration? Is the genetic toolkit required to organize body axes and facilitate organogenesis during embryogenesis the same as during regeneration? This is a particularly important question because many organisms such as the mouse, fruitfly, and frog can recover from ablation of numerous blastomeres or substantial injury to embryonic organs, yet display limited regenerative capacities as adults.
Therefore, testing whether regulative development occurs in planarian embryos, for example, may help us identify key differences crucial to preserving regenerative abilities into adulthood.
These and many more fascinating questions abound [ 8 ], so it is clear that when it comes to regeneration, we have but just begun to scratch the surface. Weismann A: The Germ-Plasm. A Theory of Heredity. Google Scholar.
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Mol Phylogenet Evol. Download references. You can also search for this author in PubMed Google Scholar. Reprints and Permissions. BMC Biol 10, 88 Download citation. Received : 12 October Accepted : 02 November Published : 08 November Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.
The molecular processes behind this are not yet known. Planarians flatworms are an extreme example of an exceptionally good regenerative capacity. They possess a large amount of somatic stem cells, which allows them to completely regenerate their body after any injury within a few days. During this regeneration process, planarians have a high demand for new cells to form new tissue through rapid stem cell division.
Regeneration is thus a very energy-consuming process that requires the animals to allocate enormous resources. Also noteworthy is the fact that planarians are able to survive prolonged periods of starvation unharmed. To do this, they maintain the relative number of their stem cells.
This means that they can regenerate in the same way as fed planarians. The maintenance of stem cells during starvation is therefore a special strategy to enable faster growth, e. However, the molecular processes required to maintain regeneration during starvation are not yet known.
To determine the transcriptional profiles of planarian stem cells in different nutritional states, FACS analysis was used to sort their stem cells and compare them between the different states to decipher regulators of regeneration during starvation. Daniel A. Maintaining proteostasis is essential for proper cell functionality. It is regulated by the proteostasis network, which coordinates protein folding, transport and degradation, among other functions. This network is severely affected by aging processes, but some of the proteostasis functions such as protein folding or degradation are increasingly strengthened, for example, by caloric restriction diet , which can also extend lifespan.
TRiC TCP1 ring complex is a chaperonin that helps in protein folding, prevents aggregation of misfolded proteins and is part of the proteostasis network. Further studies by the researchers showed that CCT subunits are primarily required for stem cell division mitotic fidelity during regeneration and TRiC exerts this function by regulating the unfolded protein response UPR at the endoplasmic reticulum ER.
ER is another component of the proteostasis network and the site where protein biosynthesis, folding and maturation occurs. Rudolph's lab, Dr. The researchers therefore propose a model in which CCT subunits are upregulated in response to starvation, and this stress response in turn activates the UPR, which subsequently increases regenerative capacity. Future research will reveal whether this is a mechanism that is also activated in stem cells under other stress types and could explain the immortality of planarians," summarizes Dr.
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