Adult teleost fish and urodele amphibians can regenerate entire amputated appendages. By contrast, regenerative healing of adult mammalian limbs is limited to the very tips of digits. One of the key challenges in developmental biology is to understand how and why tissue regeneration occurs. The hallmark of limb or fin regeneration is formation of a blastema, a mesenchymal structure that contains progenitor cells for new skeletal elements. As regeneration proceeds, blastemal cell proliferation and patterning are regulated such that lost tissues of correct size and shape are replaced, a phenomenon called positional memory. Skeletal osteoblasts in the blastema and, ultimately, the regenerated fin rays, derive from the proliferation of pre- existing osteoblasts, while an alternative source(s exists if the primary osteoblast source is disabled. Activating and inhibitory factors influence regenerative growth, and region-specific maintenance of patterning transcription factors in fin cells throughout life is a component of positional memory. Despite recent advances in our understanding of appendage regeneration, there remain key deficiencies in the field. First, there have been no published attempts to image and quantify the in vivo dynamics of cell proliferation during appendage regeneration, analyses that would illuminate how complex pattern is restored after injury. Second, a limited set of traditional developmental signaling factors has been assessed for function during regeneration. The overall goal of this proposal is to define mechanisms that regulate cell proliferation as size and pattern are restored to an amputated appendage. 1) We will apply new technologies to monitor in vivo cell cycle progression and growth indicators in transgenic zebrafish, to create a spatiotemporal map of cell proliferation during fin regeneration. 2) We will use new reagents to define whether and how signaling by the secreted factor Leptin influences zebrafish fin regeneration. 3) We will define mechanisms by which two genes implicated from a mutagenesis screen, the extracellular matrix component laminin beta 1a and the voltage-gated calcium channel calcium homeostasis modulator 1, influence fin regeneration. With these approaches, we will test the hypothesis that blastemal cell proliferation is controlled by a complex microenvironment of activating and inhibitory influences. This work will increase understanding of developmental regulation during vertebrate tissue regeneration, and provide important perspective for comprehending, and perhaps changing, the existing limitations in regenerative capacity of human tissues.
This work will increase understanding of developmental regulation during vertebrate tissue regeneration, and provide important perspective for comprehending, and perhaps changing, the existing limitations in regenerative capacity of human tissues.
|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|
Showing the most recent 10 out of 14 publications