David L Stocum, Indiana University‐Purdue University, Indianapolis, Indiana, USA
Published online: September 2009
DOI: 10.1002/9780470015902.a0001100.pub3
Urodele limbs regenerate via a blastema of progenitor cells derived from differentiated limb cells by a process of dedifferentiation. The blastema grows by mitosis of the progenitor cells under the influence of factors supplied by the wound epidermis and nerves, and is patterned into the new limb structures by molecular interactions between blastema cells.
Keywords: blastema formation; cell cycling; patterning mechanisms; retinoic acid; Hox genes
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Figure 1. Three stages of regeneration in a larval urodele forelimb amputated through the distal humerus (H). (a) One week postamputation; E, epidermis. Dedifferentiation of humeral cartilage, muscle (angled lines), dermis (oval cells beneath the epidermis) and Schwann cells (not shown) and mitosis of the dedifferentiated cells has produced a conical blastema. The mesenchyme (blastema) cells are covered by an undifferentiated wound epidermis that migrated over the wound surface within a few hours after amputation. Nerve axons have regenerated into the blastema by this stage. (b) The blastema is elongating and is about to begin redifferentiation. (c) The blastema continues to grow as it redifferentiates into the missing structures. The stippled region represents the emerging distal end of the humerus, which splits into a short radius and ulna, followed by an arch of precarpal tissue and the rudiments of the four digits of the hand. Small oval cells around and between the new cartilage condensations represent cells that will form new muscle and dermis.
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Figure 2. Diagram of in vivo affinophoresis assay. Conical blastemas (triangle) derived from the wrist (W) or elbow (E) of the axolotl forelimb were grafted to the blastema-stump junction (green arrow) on the dorsal side of a hindlimb regenerating from the mid-femur (F), and allowed to develop. The three segments of the hindlimb are depicted as rectangles. F, femur; T/f, tibia/fibula; Fo, foot; A, ankle joint and K, knee joint. The outline of the blastema at the start of the experiment is shown by the black arc. Dorsal is to the top, posterior towards the reader. As the hindlimb blastema grew and formed the segments of the hindlimb distal to the amputation plane, untreated elbow and wrist blastemas moved distally along the proximodistal axis to their corresponding levels of knee and ankle, respectively, and developed according to their level of origin. Retinoic acid treatment proximalized the positional identity of the elbow and wrist blastemas. Proximalization abolished the distal sorting behaviour of the grafted blastemas, which remained at the level of grafting and developed shoulder girdle, humerus, radius/ulna and hand.
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| References | |
| Agata K, Saito Y and Nakajima E (2007) Unifying principles of regeneration I: epimorphosis versus morphallaxis. Development Growth and Differentiation 54: 73–78. | |
| Brockes JP (1984) Mitogenic growth factors and nerve dependence of limb regeneration. Science 225: 1280–1287. | |
| Cadinouche MZA, Liversage RA, Muller W and Silfidis C (1999) Molecular cloning of the Notophthalmus viridescens radical fringe cDNA and characterization of its expression. Developmental Dynamics 214: 259–268. | |
| Chew K and Cameron JA (1983) Increase in mitotic activity of regenerating axolotl limbs by growth factor-impregnated implants. Journal of Experimental Zoology 226: 325–329. | |
| Christensen RN, Weinstein M and Tassava RA (2002) Expression of fibroblast growth factors 4, 8, and 10 in limbs, flanks, and blastemas of Ambystoma. Developmental Dynamics 223: 193–203. | |
| Crawford K and Stocum DL (1988a) Retinoic acid coordinately proximalizes regenerate pattern and blastema differential affinity in axolotl limbs. Development 102: 687–698. | |
| Crawford K and Stocum DL (1988b) Retinoic acid proximalizes level-specific properties responsible for intercalary regeneration in axolotl limbs. Development 104: 703–712. | |
| Crawford K and Vincenti DM (1998) Retinoic acid and thyroid hormone may function through similar and competitive pathways in regenerating axolotls. Journal of Experimental Zoology 282: 724–738. | |
| Dent JN (1962) Limb regeneration in larvae and metamorphosing individuals of the South African clawed toad. Journal of Morphology 110: 61–78. | |
| Ding S and Schultz PG (2004) A role for chemistry in stem cell biology. Nature Biotechnology 22: 833–840. | |
| Endo T, Yokoyama H, Tamura K and Ide Hiroyuki (1997) Shh expression in developing and regenerating limb buds of Xenopus laevis. Developmental Dynamics 209: 227–232. | |
| Ferretti P and Brockes JP (1991) Cell origin and identity in limb regeneration and development. Glia 4: 214–224. | |
| Gardiner DM, Blumberg B, Komine Y and Bryant SV (1995) Regulation of HoxA expression in developing and regenerating axolotls. Development 121: 1731–1741. | |
| Go MJ, Eastman DS and Artavanis-Tsakonas S (1998) Cell proliferation control by Notch signalling in Drosophila development. Development 125: 2031–2040. | |
| Han M-J, An J-Y and Kim W-S (2001) Expression patterns of Fgf-8 during development and limb regeneration of the axolotl. Developmental Dynamics 220: 40–48. | |
| Imokawa Y and Brockes JP (2003) Selective activation of thrombin is a critical determinant for vertebrate lens regeneration. Current Biology 13: 877–881. | |
| Imokawa Y and Yoshizato K (1997) Expression of sonic hedgehog gene in regenerating newt limb blastemas recapitulates that in developing limb buds. Proceedings of the National Academy of Sciences of the USA 94: 9159–9164. | |
| Irvin B and Tassava R (1998) Effects of peripheral nerve implants on the regeneration of partially and fully innervated urodele forelimbs. Wound Repair and Regeneration 6: 382–387. | |
| Ju BG and Kim WS (1994) Pattern duplication by retinoic acid treatment in the regenerating limbs of Korean salamander larvae, Hynobius leechi, correlates well with the extent of dedifferentiation. Developmental Dynamics 199: 253–267. | |
| Ju BG and Kim WS (1998) Upregulation of cathepsin D expression in the dedifferentiating salamander limb regenerates and enhancement of its expression by retinoic acid. Wound Repair and Regeneration 6: 349–357. | |
| Kumar A, Velloso C, Imokawa Y and Brockes JP (2000) Plasticity of retrovirus-labelled myotubes in the newt regeneration blastema. Developmental Biology 218: 125–136. | |
| Kumar A, Godwin JW, Gates PB, Garza-Garcia A and Brockes JP (2007) Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate. Science 318: 772–777. | |
| Maden M (1998) Retinoids as endogenous components of the regenerating limb and tail. Wound Repair and Regeneration 6: 358–365. | |
| Mescher AL (1992) Trophic activity of regenerating peripheral nerve. Comments on Developmental Neurobiology 1: 373–390. | |
| Miyazaki K, Uchiyama K, Imokawa Y and Yoshizato K (1996) Cloning and characterization of cDNAs for matrix metalloproteinases of regenerating newt limbs. Proceedings of the National Academy of Sciences of the USA 93: 6819–6824. | |
| Morais da Silva S, Gates PB and Brockes JB (2002) The newt ortholog of CD59 is implicated in proximodistal identity during amphibian limb regeneration. Developmental Cell 3: 547–555. | |
| Morrison JI, Loof S, He P and Simon A (2006) Salamander limb regeneration involves the activation of a multipotent skeletal muscle satellite cell population. Journal of Cell Biology 172: 433–440. | |
| Muneoka K, Fox WF and Bryant SV (1986) Cellular contribution from dermis and cartilage to the regenerating limb blastema in axolotls. Developmental Biology 116: 256–260. | |
| Odelberg SJ, Kollhof A and Keating M (2001) Dedifferentiation of mammalian myotubes induced by msx-1. Cell 103: 1099–1109. | |
| Poulin ML, Patrie KM, Botelho MJ, Tassava RA and Chiu I-M (1993) Heterogeneity in expression of fibroblast growth factor receptors during limb regeneration in newts (Notophthalmus viridescens). Development 119: 353–361. | |
| Shimizu–Nishikawa KS, Tsuji S and Yoshizato K (2001) Identification and characterization of newt rad (ras associated with diabetes), a gene specifically expressed in regenerating limb muscle. Developmental Dynamics 220: 74–86. | |
| Simon H-G, Kittappa R, Khan PA et al. (1997) A novel family of T-box genes in urodele amphibian development and regeneration: candidate genes involved in vertebrate forelimb/hindlimb patterning. Development 124: 1355–1366. | |
| Simon H-G, Nelson C, Goff D et al. (1995) Differential expression of myogenic regulatory genes and Msx-1 during dedifferentiation and redifferentiation of regenerating amphibian limbs. Developmental Dynamics 202: 1–12. | |
| Singer M (1952) The influence of the nerve in regeneration of the amphibian extremity. Quarterly Review of Biology 27: 169–200. | |
| Stark DR, Gates PB, Brockes JP and Ferretti P (1998) Hedgehog family member is expressed throughout regenerating and developing limbs. Developmental Dynamics 212: 352–363. | |
| Steen TP (1968) Stability of chondrocyte differentiation and contribution of muscle to cartilage during limb regeneration in the axolotl (Siredon mexicanum). Journal of Experimental Zoology 167: 49–78. | |
| book Stocum DL (1985) "The role of the skin in urodele limb regeneration". In: Sicard R (ed.) Control of Forelimb Regeneration, pp. 32–53. Oxford: Oxford University Press. | |
| Stocum DL (1996) A conceptual framework for analyzing axial patterning in regenerating urodele limbs. International Journal of Developmental Biology 40: 773–783. | |
| Stocum DL and Zupanc GKH (2008) Stretching the limits: stem cells in regeneration science. Developmental Dynamics 237: 3648–3671. | |
| Suzuki M, Yakushiji N, Nalada Y et al. (2006) Limb regeneration in Xenopus laevis froglet. Scientific World Journal 6(suppl. 1): 26–37. | |
| Takahashi K, Tanabe K, Ohnuki M et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861–872. | |
| Tanaka EM, Dreschel N and Brockes JP (1999) Thrombin regulates S phase re-entry by cultured newt myoblasts. Current Biology 9: 792–799. | |
| Tanaka EM, Gann AAF, Gates PB and Brockes JB (1997) Newt myotubes reenter the cell cycle by phosphorylation of the retinoblastoma protein. Journal of Cell Biology 136: 155–165. | |
| Torok M, Gardiner DM, Shubin NH and Bryant SV (1998) Expression of HoxD genes in developing and regenerating axolotl limbs. Developmental Biology 200: 225–233. | |
| Vinarsky V, Atkinson DL, Stevenson T, Keating MT and Odelberg SJ (2005) Normal newt limb regeneration requires matrix metalloproteinase function. Developmental Biology 279: 86–98. | |
| Wada N, Kimura I, Tanaka H, Ide H and Nohno T (1998) Glycosylphosphatidylinositol-anchored cell surface proteins regulate position-specific cell affinity in the limb bud. Developmental Biology 202: 244–252. | |
| Wolfe AD, Nye HLD and Cameron JA (2000) Extent of ossification at the amputation plane is correlated with the decline of blastema formation and regeneration in Xenopus laevis hindlimbs. Developmental Dynamics 218: 681–697. | |
| Yajima H, Yonei-Tamura S, Watanabe N, Tamura K and Ide H (1999) Role of N-cadherin in the sorting out of mesenchymal cells and in the positional identity along the proximodistal axis of the chick limb bud. Developmental Dynamics 216: 274–284. | |
| Yang EV and Bryant SV (1994) Developmental regulation of a matrix metalloproteinase during regeneration of axolotl appendages. Developmental Biology 166: 696–703. | |
| Yu J, Vodyanik MA, Smuga-Otto K et al. (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917–1920. | |
| Further Reading | |
| Brockes JP (1997) Amphibian limb regeneration: rebuilding a complex structure. Science 276: 81–87. | |
| Brockes JP and Kumar A (2002) Plasticity and reprogramming of differentiated cells in amphibian regeneration. Nature Reviews of Molecular and Cell Biology 3: 566–574. | |
| book Carlson BM (2007) Principles of Regenerative Biology, 379 pp. San Diego: Elsevier/Academic Press. | |
| Gardiner DM, Carlson MRJ and Roy S (1999) Towards a functional analysis of limb regeneration. Seminars in Cell and Developmental Biology 10: 385–394. | |
| Geraudie J and Ferretti P (1998) Gene expression during amphibian limb regeneration. International Review of Cytology 180: 1–49. | |
| Mescher AL (1996) The cellular basis of limb regeneration in urodeles. International Journal of Developmental Biology 40: 785–796. | |
| book Stocum DL (2006) Regenerative Biology and Medicine, 465 pp. San Diego: Elsevier/Academic Press. | |
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