Planarian flatworms are famous for their ability to rapidly regenerate new heads or even entire organisms from a fragment 1/300th the size of the original animal. Planarian regeneration involves stem cells (neoblasts) that produce every cell of the animal. Despite centuries of fascination with regeneration, mechanistic explanations await elucidation. The broad, long-term objectives of this proposal are to use planarians as a model system to identify and understand the molecular mechanisms that regulate stem cells to promote regeneration.
The specific aims are 1) to characterize the mode of action of the neoblast regulatory SMEDWI-2 protein, 2) to determine the function of genes previously determined to be needed for regeneration, and 3) to utilize RNAi screening strategies and genome resources to identify the key genes that control neoblasts for regeneration. Stem cells and regenerative biology are the subjects of recent and intense interest for regenerative medicine. In addition, the misregulation of stem cells may be central to many types of cancer. A newly developed arsenal of tools for molecular genetic study of planarians now exists. For example, systematic gene perturbation with RNA interference (RNAi) is now possible and the planarian genome is being sequenced. Greater than half of planarian genes have counterparts in the human genome;therefore, planarian studies should identify conserved stem cell regulatory genes. SMEDWI-2 is similar to PIWI-like RNA binding proteins, expressed in neoblasts, and needed for regeneration. Mammalian piwi-like genes regulate germline stem cells and can be overexpressed in cancers.
Aim #1 will examine neoblast progeny cell differentiation and survival in smedwi-2(RNAi) animals and characterize the site of SMEDWI-2 action. Experiments of Aim #2 will identify roles for ten genes, which have been already determined to be important for regeneration, in one of three processes: neoblast activation following wounding, neoblast progeny cell differentiation, and/or neoblast maintenance. Methods employed include RNAi and established neoblast labeling approaches. The time and site of expression of these genes in regeneration will be determined with in situ hybridizations and RT-PCR. With well-developed tools and planarian genome resources now in hand for the first time, Aim #3 will use RNAi to identify key planarian regeneration genes. Project Narrative: Stem cells are important for public health because they are essential for the growth and maintenance of tissues and lie at the heart of many cancers. Additionally, many regenerative medicine strategies propose the utilization of stem cells to replace missing or undesirable cells. Planarians present a new and powerful system to identify existing molecular mechanisms that regulate stem cells for regeneration.
Stem cells are important for public health because they are essential for the growth and maintenance of tissues and lie at the heart of many cancers. Additionally, many regenerative medicine strategies propose the utilization of stem cells to replace missing or undesirable cells. Planarians present a new and powerful system to identify existing molecular mechanisms that regulate stem cells for regeneration.
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| Atabay, Kutay Deniz; LoCascio, Samuel A; de Hoog, Thom et al. (2018) Self-organization and progenitor targeting generate stable patterns in planarian regeneration. Science 360:404-409 |
| Scimone, M Lucila; Cote, Lauren E; Reddien, Peter W (2017) Orthogonal muscle fibres have different instructive roles in planarian regeneration. Nature 551:623-628 |
| LoCascio, Samuel A; Lapan, Sylvain W; Reddien, Peter W (2017) Eye Absence Does Not Regulate Planarian Stem Cells during Eye Regeneration. Dev Cell 40:381-391.e3 |
| Oderberg, Isaac M; Li, Dayan J; Scimone, M Lucila et al. (2017) Landmarks in Existing Tissue at Wounds Are Utilized to Generate Pattern in Regenerating Tissue. Curr Biol 27:733-742 |
| Wurtzel, Omri; Oderberg, Isaac M; Reddien, Peter W (2017) Planarian Epidermal Stem Cells Respond to Positional Cues to Promote Cell-Type Diversity. Dev Cell 40:491-504.e5 |
| Wang, Irving E; Lapan, Sylvain W; Scimone, M Lucila et al. (2016) Hedgehog signaling regulates gene expression in planarian glia. Elife 5: |
| Scimone, M Lucila; Cote, Lauren E; Rogers, Travis et al. (2016) Two FGFRL-Wnt circuits organize the planarian anteroposterior axis. Elife 5: |
| Wurtzel, Omri; Cote, Lauren E; Poirier, Amber et al. (2015) A Generic and Cell-Type-Specific Wound Response Precedes Regeneration in Planarians. Dev Cell 35:632-645 |
| Owen, Jared H; Wagner, Daniel E; Chen, Chun-Chieh et al. (2015) teashirt is required for head-versus-tail regeneration polarity in planarians. Development 142:1062-72 |
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