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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM080639-05
Application #
8230606
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Haynes, Susan R
Project Start
2008-03-20
Project End
2013-06-06
Budget Start
2012-03-01
Budget End
2013-06-06
Support Year
5
Fiscal Year
2012
Total Cost
$294,268
Indirect Cost
$143,361
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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Scimone, M Lucila; Kravarik, Kellie M; Lapan, Sylvain W et al. (2014) Neoblast specialization in regeneration of the planarian Schmidtea mediterranea. Stem Cell Reports 3:339-52
van Wolfswinkel, Josien C; Wagner, Daniel E; Reddien, Peter W (2014) Single-cell analysis reveals functionally distinct classes within the planarian stem cell compartment. Cell Stem Cell 15:326-39
Witchley, Jessica N; Mayer, Mirjam; Wagner, Daniel E et al. (2013) Muscle cells provide instructions for planarian regeneration. Cell Rep 4:633-41
Chen, Chun-Chieh G; Wang, Irving E; Reddien, Peter W (2013) pbx is required for pole and eye regeneration in planarians. Development 140:719-29
Wenemoser, Danielle; Lapan, Sylvain W; Wilkinson, Alex W et al. (2012) A molecular wound response program associated with regeneration initiation in planarians. Genes Dev 26:988-1002
Wagner, Daniel E; Ho, Jaclyn J; Reddien, Peter W (2012) Genetic regulators of a pluripotent adult stem cell system in planarians identified by RNAi and clonal analysis. Cell Stem Cell 10:299-311
Scimone, M Lucila; Srivastava, Mansi; Bell, George W et al. (2011) A regulatory program for excretory system regeneration in planarians. Development 138:4387-98
Wagner, Daniel E; Wang, Irving E; Reddien, Peter W (2011) Clonogenic neoblasts are pluripotent adult stem cells that underlie planarian regeneration. Science 332:811-6
Reddien, Peter W (2011) Constitutive gene expression and the specification of tissue identity in adult planarian biology. Trends Genet 27:277-85

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