SHANNON J. ODELBERG
|Assistant Professor of Internal Medicine
Assistant Professor of Neurobiology and Anatomy
Odelberg Laboratory Home Page
Molecular basis of regeneration and cellular plasticity
Newts have the remarkable ability to regenerate several anatomical structures and organs including their limbs, spinal cords, hearts, tails, retinas, lenses, and upper and lower jaws. These regenerative processes are dependent upon the dedifferentiation of cells in the vicinity of the amputation site or injured organ. This degree of cellular plasticity is unique to vertebrates with marked regenerative abilities and is not observed in mammals. My laboratory is interested in identifying the genes that regulate this cellular plasticity with the hope of applying this knowledge to enhance the regenerative capacity in mammals. We are especially interested in studying the molecular pathways that control spinal cord, heart, and limb regeneration.
We have recently found that factors present in regenerating newt limbs, but absent in nonregenerating limbs, can induce both newt and mouse myotubes to dedifferentiate. This activity is destroyed by excessive heat, repeated freeze-thaw cycles, and trypsin treatment, suggesting that proteins are a required component of the dedifferentiation signal. These results indicate that the signaling pathways controlling cellular 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 dedifferentiation-initiating signals. We are attempting to identify these extracellular signals by performing differential expression analyses between regenerating and nonregenerating newt limbs. Using such an approach, we have identified over 200 genes that appear to be transcriptionally upregulated during the first day of limb regeneration and have cloned full-length cDNAs for more than 130 of these genes. We are presently confirming the differential expression patterns of these candidate genes and are beginning to use functional assays to determine whether these genes can initiate cellular dedifferentiation. An expression cloning strategy is also being employed to identify a gene that initiates cell cycle reentry during the dedifferentiation process. In vivo methods for testing the function of these genes during limb regeneration are currently being developed.
We have also recently shown that ectopic expression of the homeobox gene, msx1, can induce mouse myotubes to dedifferentiate to a proliferating multipotent cell type. When stimulated with the appropriate signals, these dedifferentiated cells can redifferentiate into multiple cell types including those expressing chondrogenic, adipogenic, osteogenic, and myogenic markers. Msx genes are expressed in early limb and fin regenerates in newts, axolotls, and zebrafish and are thought to play a critical role in the regenerative process. The fact that we have been able to induce dedifferentiation of mammalian myotubes by expressing msx1 suggests that the role of msx genes in regeneration may be to induce and maintain cellular plasticity. We are performing both in vitro and in vivo experiments to determine whether msx1 can induce cellular plasticity in other cell types as well and whether induced expression of msx1 can elicit a regenerative response in mammals.
Atkinson, D.L., Stevenson, T.J., Park, E.J., Riedy, M.D., Milash, B., and Odelberg, S.J. (2006) Cellular electroporation induces dedifferentiation in intact newt limbs. Developmental Biology, 299:257-271.
Stevenson, T.J., Vinarsky, V., Atkinson, D.L., Keating, M.T., and Odelberg, S.J. (2006) Tissue inhibitor of metalloproteinase 1 regulates matrix metalloproteinase activity during newt limb regeneration. Developmental Dynamics, 235:606-616.
Vinarsky, V., Atkinson, D.L., Stevenson, T.J., Keating, M.T., and Odelberg, S.J. (2005) Normal newt limb regeneration requires matrix metalloproteinase function. Dev. Biol., 279:86-98.
Odelberg, S.J. (2004) Unraveling the molecular basis for regenerative cellular plasticity. PLoS Biol., 2:1068-1071.
Odelberg, S.J. (2002) Inducing cellular dedifferentiation: a potential method for enhancing endogenous regeneration in mammals. Sem Cell Dev Biol, 13:335-343.
McGann, C.J., Odelberg, S.J., and Keating, M.T. (2001) Mammalian myotube dedifferentiation induced by newt regeneration extract. Proc Natl Acad Sci USA, 98:13699-13704.
Odelberg, S.J., Kollhoff, A., and Keating, M.T. (2000) Dedifferentiation of mammalian myotubes induced by msx1. Cell, 103:1099-1109.