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
Tornini, Valerie A; Poss, Kenneth D (2014) Keeping at arm's length during regeneration. Dev Cell 29:139-45
Johnson, Aaron N; Mokalled, Mayssa H; Valera, Juliana M et al. (2013) Post-transcriptional regulation of myotube elongation and myogenesis by Hoi Polloi. Development 140:3645-56
Kang, Junsu; Nachtrab, Gregory; Poss, Kenneth D (2013) Local Dkk1 crosstalk from breeding ornaments impedes regeneration of injured male zebrafish fins. Dev Cell 27:19-31
Le, Xiuning; Pugach, Emily K; Hettmer, Simone et al. (2013) A novel chemical screening strategy in zebrafish identifies common pathways in embryogenesis and rhabdomyosarcoma development. Development 140:2354-64
Nachtrab, Gregory; Kikuchi, Kazu; Tornini, Valerie A et al. (2013) Transcriptional components of anteroposterior positional information during zebrafish fin regeneration. Development 140:3754-64
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
Singh, Sumeet Pal; Holdway, Jennifer E; Poss, Kenneth D (2012) Regeneration of amputated zebrafish fin rays from de novo osteoblasts. Dev Cell 22:879-86
Nachtrab, Gregory; Czerwinski, Michael; Poss, Kenneth D (2011) Sexually dimorphic fin regeneration in zebrafish controlled by androgen/GSK3 signaling. Curr Biol 21:1912-7
Qin, Zhao; Kidd 3rd, Ambrose R; Thomas, Jennifer L et al. (2011) FGF signaling regulates rod photoreceptor cell maintenance and regeneration in zebrafish. Exp Eye Res 93:726-34
Lee, Yoonsung; Hami, Danyal; De Val, Sarah et al. (2009) Maintenance of blastemal proliferation by functionally diverse epidermis in regenerating zebrafish fins. Dev Biol 331:270-80

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