Adult teleost fish and urodele amphibians have the capacity to regenerate entire amputated appendages. In striking contrast, regenerative healing of mammalian limbs is limited to the very tips of digits. During limb regeneration in urodeles and fin regeneration in teleosts, regeneration is precisely regulated such that only the appropriate structures are replaced. One of the classic and unexplained questions of appendage regeneration is how adult cells in the injured area retain or recognize the positional information necessary to accomplish this. The central questions by which this """"""""positional memory"""""""" is maintained are these. First, to what extent do cells retain their lineage restriction and state of differentiation during regeneration? That is, are differentiated adult cells of one lineage able to contribute to one or more other lineages, or to assume a less differentiated form? Second, which specific molecular programs are essential for retaining and regulating positional information within these cells? Here, we propose to define new cellular and molecular regulatory mechanisms that maintain positional information and instruct regenerative renewal of zebrafish fins, complex organs containing bone, connective tissue mesenchyme, epidermis, blood vessels, nerves, and pigment cells. In this proposal, we describe a programmatic approach to positional memory, using 1) new technology for the lineage tracing of adult fin cells;2) candidate gene testing based on new results;and 3) a forward genetic approach of mutagenesis screening and positional cloning. With this approach, we will test the hypothesis that differentiated adult appendage tissues express region-specific profiles of regulatory factors that maintain positional information important for regenerative fidelity. Our molecular genetic approach will increase understanding of regulatory mechanisms active during regenerative organogenesis, and provide important perspective for comprehending, and perhaps changing, the existing limitations in regenerative capacity of most human organs.

Public Health Relevance

Our molecular genetic approach will increase understanding of regulatory mechanisms active during regenerative organogenesis, and provide important perspective for comprehending, and perhaps changing, the existing limitations in regenerative capacity of most human organs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM074057-07
Application #
8293216
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Haynes, Susan R
Project Start
2006-05-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
7
Fiscal Year
2012
Total Cost
$282,604
Indirect Cost
$94,504
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Han, Yanchao; Poss, Kenneth D (2016) Accessories to Limb Regeneration. Dev Cell 37:297-8
Nichols, James T; Blanco-Sánchez, Bernardo; Brooks, Elliott P et al. (2016) Ligament versus bone cell identity in the zebrafish hyoid skeleton is regulated by mef2ca. Development 143:4430-4440
Tornini, Valerie A; Puliafito, Alberto; Slota, Leslie A et al. (2016) Live Monitoring of Blastemal Cell Contributions during Appendage Regeneration. Curr Biol 26:2981-2991
Kang, Junsu; Hu, Jianxin; Karra, Ravi et al. (2016) Modulation of tissue repair by regeneration enhancer elements. Nature 532:201-6
Chen, Chen-Hui; Merriman, Alexander F; Savage, Jeremiah et al. (2015) Transient laminin beta 1a Induction Defines the Wound Epidermis during Zebrafish Fin Regeneration. PLoS Genet 11:e1005437
Kang, Junsu; Karra, Ravi; Poss, Kenneth D (2015) Back in Black. Dev Cell 33:623-4
Tornini, Valerie A; Poss, Kenneth D (2014) Keeping at arm's length during regeneration. Dev Cell 29:139-45
Gemberling, Matthew; Bailey, Travis J; Hyde, David R et al. (2013) The zebrafish as a model for complex tissue regeneration. Trends Genet 29:611-20

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