Assistant Professor of Neurobiology and Anatomy and of Internal medicine
B.S. Weber State University
Ph.D. Virginia Commonwealth University
Newts have the remarkable ability to regenerate several anatomical structures and organs including their limbs, spinal cords, hearts, tails, retinas, lenses, optic nerves, intestines, and upper and lower jaws. Many of the progenitor cells that are required for regeneration are created de novo by the dedifferentiation of mature cells located near the site of injury. This degree of cellular plasticity is unique to organisms with marked regenerative abilities and is not observed in mammals. My laboratory is interested in identifying the genes that regulate cellular plasticity with the hope of someday applying this knowledge to enhance the regenerative capacity in mammals. We are currently focusing our efforts on identifying the genes that regulate limb and spinal cord regeneration.
We have found that proteins present in regenerating newt limbs, but absent in intact limbs, can induce both newt and mouse myotubes to dedifferentiate. These results indicate that the intracellular signaling pathways controlling dedifferentiation are intact in at least some mammalian cells and suggest that the lack of cellular plasticity in mammals may be due to the absence of extracellular signals capable of initiating the dedifferentiation process. In an effort to identify these extracellular signals, we have performed differential expression analyses between regenerating and intact newt limbs and have cloned the full-length open reading frames of more than 130 upregulated genes.
Based on this initial screen, we have focused our efforts on two classes of extracellular proteins that are excellent candidates for initiating dedifferentiation: 1) matrix metalloproteinases (MMPs) and 2) cytokines. Inhibition of MMP function leads to abnormal limb regenerates, suggesting that MMPs are required for normal limb regeneration. My laboratory is actively involved in identifying which MMPs are required for limb regeneration and in elucidating the biochemical and cellular mechanisms of MMP function during limb regeneration. We have also identified several putative cytokine genes that are upregulated during the initial stages of limb regeneration, and we are testing these genes for function using a variety of cell culture assays. Methods for assessing the function of candidate genes in vivo are being developed, including inducible transgene expression and knockdown of gene expression in newt limbs.
An adult newt can also regenerate its spinal cord following either complete transection or ablation. Two cellular responses are thought to be critical for newt spinal cord regeneration: 1) a robust and controlled ependymal cell response and 2) axon regrowth through special channels formed by cytoplasmic processes that extend from the basal ends of the ependymal cells to the pia mater. In addition, the lack of a glial scar at the lesion site allows the regenerating axons to grow through the lesion and make the appropriate connections for functional recovery. We have identified several candidate genes that are upregulated during newt spinal cord regeneration and might function to induce the ependymal cell response, promote axon regrowth, or prevent glial scar formation. We are currently assessing the function of these candidate genes in the regenerative process..
Newt limb and spinal cord regeneration. Left panel. An adult newt forelimb regenerates in 7-10 weeks following amputation through the stylopod. Right panel. An adult newt can regenerate a completely transected spinal cord and regain function in less than 10 weeks. Arrow indicates lesion site (shown as a gap in the middle photograph) that contains regenerated neural tissue at 10 weeks post-injury.
1. Atkinson DL, Stevenson TJ, Park EJ, Riedy MD, Milash B, Odelberg SJ (2006) Cellular electroporation induces dedifferentiation in intact newt limbs. Dev Biol 299:257-271
2. Stevenson TJ, Vinarsky V, Atkinson DL, Keating MT, Odelberg SJ (2006) Tissue inhibitor of metalloproteinase 1 regulates matrix metalloproteinase activity during newt limb regeneration. Dev Dyn 235:606-616
3. Vinarsky V, Atkinson DL, Stevenson TJ, Keating MT, Odelberg SJ (2005) Normal newt limb regeneration requires matrix metalloproteinase function. Dev Biol 279:86-98
4. Odelberg SJ (2005) Cellular plasticity in vertebrate regeneration. Anat Rec B New Anat 287:25-35
5. Odelberg SJ (2004) Unraveling the molecular basis for regenerative cellular plasticity. PLoS Biol 2:1068-1071
6. Odelberg SJ (2002) Inducing cellular dedifferentiation: a potential method for enhancing endogenous regeneration in mammals. Sem Cell Devel Biol 13:335-343
7. McGann CJ, Odelberg SJ, Keating MT (2001) Mammalian myotube dedifferentiation induced by newt regeneration extract. Proc Natl Acad Sci USA 98:13699-13704
8. Odelberg SJ, Kollhoff A, Keating MT (2000) Dedifferentiation of mammalian myotubes induced by msx1. Cell 103:1099-1109