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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2004 May 29;359(1445):759–763. doi: 10.1098/rstb.2004.1465

Regeneration and the need for simpler model organisms.

Alejandro Sánchez Alvarado 1
PMCID: PMC1693366  PMID: 15293803

Abstract

The problem of regeneration is fundamentally a problem of tissue homeostasis involving the replacement of cells lost to normal 'wear and tear' (cell turnover), and/or injury. This attribute is of particular significance to organisms possessing relatively long lifespans, as maintenance of all body parts and their functional integration is essential for their survival. Because tissue replacement is broadly distributed among multicellular life-forms, and the molecules and mechanisms controlling cellular differentiation are considered ancient evolutionary inventions, it should be possible to gain key molecular insights about regenerative processes through the study of simpler animals. We have chosen to study and develop the freshwater planarian Schmidtea mediterranea as a model system because it is one of the simplest metazoans possessing tissue homeostasis and regeneration, and because it has become relatively easy to molecularly manipulate this organism. The developmental plasticity and longevity of S. mediterranea is in marked contrast to its better-characterized invertebrate cohorts: the fruitfly Drosophila melanogaster and the roundworm Caenorhabditis elegans, both of which have short lifespans and are poor at regenerating tissues. Therefore, planarians present us with new, experimentally accessible contexts in which to study the molecular actions guiding cell fate restriction, differentiation and patterning, each of which is crucial not only for regeneration to occur, but also for the survival and perpetuation of all multicellular organisms.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barolo Scott, Posakony James W. Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling. Genes Dev. 2002 May 15;16(10):1167–1181. doi: 10.1101/gad.976502. [DOI] [PubMed] [Google Scholar]
  2. Boilly B., Cavanaugh K. P., Thomas D., Hondermarck H., Bryant S. V., Bradshaw R. A. Acidic fibroblast growth factor is present in regenerating limb blastemas of axolotls and binds specifically to blastema tissues. Dev Biol. 1991 Jun;145(2):302–310. doi: 10.1016/0012-1606(91)90128-p. [DOI] [PubMed] [Google Scholar]
  3. Brennecke Julius, Hipfner David R., Stark Alexander, Russell Robert B., Cohen Stephen M. bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell. 2003 Apr 4;113(1):25–36. doi: 10.1016/s0092-8674(03)00231-9. [DOI] [PubMed] [Google Scholar]
  4. Brockes J. P., Kumar A., Velloso C. P. Regeneration as an evolutionary variable. J Anat. 2001 Jul-Aug;199(Pt 1-2):3–11. doi: 10.1046/j.1469-7580.2001.19910003.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cebrià Francesc, Kobayashi Chiyoko, Umesono Yoshihiko, Nakazawa Masumi, Mineta Katsuhiko, Ikeo Kazuho, Gojobori Takashi, Itoh Mari, Taira Masanori, Sánchez Alvarado Alejandro. FGFR-related gene nou-darake restricts brain tissues to the head region of planarians. Nature. 2002 Oct 10;419(6907):620–624. doi: 10.1038/nature01042. [DOI] [PubMed] [Google Scholar]
  6. Chervitz S. A., Aravind L., Sherlock G., Ball C. A., Koonin E. V., Dwight S. S., Harris M. A., Dolinski K., Mohr S., Smith T. Comparison of the complete protein sets of worm and yeast: orthology and divergence. Science. 1998 Dec 11;282(5396):2022–2028. doi: 10.1126/science.282.5396.2022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Force A., Lynch M., Pickett F. B., Amores A., Yan Y. L., Postlethwait J. Preservation of duplicate genes by complementary, degenerative mutations. Genetics. 1999 Apr;151(4):1531–1545. doi: 10.1093/genetics/151.4.1531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fukuchi-Shimogori Tomomi, Grove Elizabeth A. Emx2 patterns the neocortex by regulating FGF positional signaling. Nat Neurosci. 2003 Aug;6(8):825–831. doi: 10.1038/nn1093. [DOI] [PubMed] [Google Scholar]
  9. Gerhart J. 1998 Warkany lecture: signaling pathways in development. Teratology. 1999 Oct;60(4):226–239. doi: 10.1002/(SICI)1096-9926(199910)60:4<226::AID-TERA7>3.0.CO;2-W. [DOI] [PubMed] [Google Scholar]
  10. Godwin A. R., Capecchi M. R. Hoxc13 mutant mice lack external hair. Genes Dev. 1998 Jan 1;12(1):11–20. doi: 10.1101/gad.12.1.11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hartwell L. H., Hopfield J. J., Leibler S., Murray A. W. From molecular to modular cell biology. Nature. 1999 Dec 2;402(6761 Suppl):C47–C52. doi: 10.1038/35011540. [DOI] [PubMed] [Google Scholar]
  12. Holland P. W. Gene duplication: past, present and future. Semin Cell Dev Biol. 1999 Oct;10(5):541–547. doi: 10.1006/scdb.1999.0335. [DOI] [PubMed] [Google Scholar]
  13. Hooper Joan E. Smoothened translates Hedgehog levels into distinct responses. Development. 2003 Sep;130(17):3951–3963. doi: 10.1242/dev.00594. [DOI] [PubMed] [Google Scholar]
  14. Imokawa Yutaka, Brockes Jeremy P. Selective activation of thrombin is a critical determinant for vertebrate lens regeneration. Curr Biol. 2003 May 13;13(10):877–881. doi: 10.1016/s0960-9822(03)00294-x. [DOI] [PubMed] [Google Scholar]
  15. Johnston L. A., Edgar B. A. Wingless and Notch regulate cell-cycle arrest in the developing Drosophila wing. Nature. 1998 Jul 2;394(6688):82–84. doi: 10.1038/27925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. King Nicole, Hittinger Christopher T., Carroll Sean B. Evolution of key cell signaling and adhesion protein families predates animal origins. Science. 2003 Jul 18;301(5631):361–363. doi: 10.1126/science.1083853. [DOI] [PubMed] [Google Scholar]
  17. Lake J. A. Origin of the Metazoa. Proc Natl Acad Sci U S A. 1990 Jan;87(2):763–766. doi: 10.1073/pnas.87.2.763. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lander E. S., Linton L. M., Birren B., Nusbaum C., Zody M. C., Baldwin J., Devon K., Dewar K., Doyle M., FitzHugh W. Initial sequencing and analysis of the human genome. Nature. 2001 Feb 15;409(6822):860–921. doi: 10.1038/35057062. [DOI] [PubMed] [Google Scholar]
  19. Lee Patricia N., Callaerts Patrick, De Couet Heinz G., Martindale Mark Q. Cephalopod Hox genes and the origin of morphological novelties. Nature. 2003 Aug 28;424(6952):1061–1065. doi: 10.1038/nature01872. [DOI] [PubMed] [Google Scholar]
  20. Lee R. C., Feinbaum R. L., Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993 Dec 3;75(5):843–854. doi: 10.1016/0092-8674(93)90529-y. [DOI] [PubMed] [Google Scholar]
  21. Li X., Noll M. Evolution of distinct developmental functions of three Drosophila genes by acquisition of different cis-regulatory regions. Nature. 1994 Jan 6;367(6458):83–87. doi: 10.1038/367083a0. [DOI] [PubMed] [Google Scholar]
  22. McGinnis W. A century of homeosis, a decade of homeoboxes. Genetics. 1994 Jul;137(3):607–611. doi: 10.1093/genetics/137.3.607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mullen L. M., Bryant S. V., Torok M. A., Blumberg B., Gardiner D. M. Nerve dependency of regeneration: the role of Distal-less and FGF signaling in amphibian limb regeneration. Development. 1996 Nov;122(11):3487–3497. doi: 10.1242/dev.122.11.3487. [DOI] [PubMed] [Google Scholar]
  24. Neumann C. J., Cohen S. M. Distinct mitogenic and cell fate specification functions of wingless in different regions of the wing. Development. 1996 Jun;122(6):1781–1789. doi: 10.1242/dev.122.6.1781. [DOI] [PubMed] [Google Scholar]
  25. Neumann C. J., Cohen S. M. Long-range action of Wingless organizes the dorsal-ventral axis of the Drosophila wing. Development. 1997 Feb;124(4):871–880. doi: 10.1242/dev.124.4.871. [DOI] [PubMed] [Google Scholar]
  26. Newmark P. A., Sánchez Alvarado A. Bromodeoxyuridine specifically labels the regenerative stem cells of planarians. Dev Biol. 2000 Apr 15;220(2):142–153. doi: 10.1006/dbio.2000.9645. [DOI] [PubMed] [Google Scholar]
  27. Newmark Philip A., Sánchez Alvarado Alejandro. Not your father's planarian: a classic model enters the era of functional genomics. Nat Rev Genet. 2002 Mar;3(3):210–219. doi: 10.1038/nrg759. [DOI] [PubMed] [Google Scholar]
  28. Odelberg S. J., Kollhoff A., Keating M. T. Dedifferentiation of mammalian myotubes induced by msx1. Cell. 2000 Dec 22;103(7):1099–1109. doi: 10.1016/s0092-8674(00)00212-9. [DOI] [PubMed] [Google Scholar]
  29. Oviedo Néstor J., Newmark Phillip A., Sánchez Alvarado Alejandro. Allometric scaling and proportion regulation in the freshwater planarian Schmidtea mediterranea. Dev Dyn. 2003 Feb;226(2):326–333. doi: 10.1002/dvdy.10228. [DOI] [PubMed] [Google Scholar]
  30. Pecorino L. T., Entwistle A., Brockes J. P. Activation of a single retinoic acid receptor isoform mediates proximodistal respecification. Curr Biol. 1996 May 1;6(5):563–569. doi: 10.1016/s0960-9822(02)00542-0. [DOI] [PubMed] [Google Scholar]
  31. Pinto Daniel, Gregorieff Alex, Begthel Harry, Clevers Hans. Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev. 2003 Jul 15;17(14):1709–1713. doi: 10.1101/gad.267103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Reinhart B. J., Slack F. J., Basson M., Pasquinelli A. E., Bettinger J. C., Rougvie A. E., Horvitz H. R., Ruvkun G. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature. 2000 Feb 24;403(6772):901–906. doi: 10.1038/35002607. [DOI] [PubMed] [Google Scholar]
  33. Robb Sofia M., Sánchez Alvarado Alejandro. Identification of immunological reagents for use in the study of freshwater planarians by means of whole-mount immunofluorescence and confocal microscopy. Genesis. 2002 Apr;32(4):293–298. doi: 10.1002/gene.10087. [DOI] [PubMed] [Google Scholar]
  34. Rubin G. M., Yandell M. D., Wortman J. R., Gabor Miklos G. L., Nelson C. R., Hariharan I. K., Fortini M. E., Li P. W., Apweiler R., Fleischmann W. Comparative genomics of the eukaryotes. Science. 2000 Mar 24;287(5461):2204–2215. doi: 10.1126/science.287.5461.2204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Ruvkun G., Hobert O. The taxonomy of developmental control in Caenorhabditis elegans. Science. 1998 Dec 11;282(5396):2033–2041. doi: 10.1126/science.282.5396.2033. [DOI] [PubMed] [Google Scholar]
  36. Schauer Stephen E., Jacobsen Steven E., Meinke David W., Ray Animesh. DICER-LIKE1: blind men and elephants in Arabidopsis development. Trends Plant Sci. 2002 Nov;7(11):487–491. doi: 10.1016/s1360-1385(02)02355-5. [DOI] [PubMed] [Google Scholar]
  37. Schopf J. W. Collapse of the Late Proterozoic ecosystem. South Afr J Geol. 1991;94(1):33–43. [PubMed] [Google Scholar]
  38. Steiling Heike, Wüstefeld Torsten, Bugnon Philippe, Brauchle Maria, Fässler Reinhard, Teupser Daniel, Thiery Joachim, Gordon Jeffrey I., Trautwein Christian, Werner Sabine. Fibroblast growth factor receptor signalling is crucial for liver homeostasis and regeneration. Oncogene. 2003 Jul 10;22(28):4380–4388. doi: 10.1038/sj.onc.1206499. [DOI] [PubMed] [Google Scholar]
  39. Sánchez Alvarado A., Newmark P. A. Double-stranded RNA specifically disrupts gene expression during planarian regeneration. Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5049–5054. doi: 10.1073/pnas.96.9.5049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sánchez Alvarado A. Regeneration in the metazoans: why does it happen? Bioessays. 2000 Jun;22(6):578–590. doi: 10.1002/(SICI)1521-1878(200006)22:6<578::AID-BIES11>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
  41. Sánchez Alvarado Alejandro, Newmark Phillip A., Robb Sofia M., Juste Réjeanne. The Schmidtea mediterranea database as a molecular resource for studying platyhelminthes, stem cells and regeneration. Development. 2002 Dec;129(24):5659–5665. doi: 10.1242/dev.00167. [DOI] [PubMed] [Google Scholar]
  42. Sánchez Alvarado Alejandro. The freshwater planarian Schmidtea mediterranea: embryogenesis, stem cells and regeneration. Curr Opin Genet Dev. 2003 Aug;13(4):438–444. doi: 10.1016/s0959-437x(03)00082-0. [DOI] [PubMed] [Google Scholar]
  43. Telford M. J. Evidence for the derivation of the Drosophila fushi tarazu gene from a Hox gene orthologous to lophotrochozoan Lox5. Curr Biol. 2000 Mar 23;10(6):349–352. doi: 10.1016/s0960-9822(00)00387-0. [DOI] [PubMed] [Google Scholar]
  44. da Silva Sara Morais, Gates Phillip B., Brockes Jeremy P. The newt ortholog of CD59 is implicated in proximodistal identity during amphibian limb regeneration. Dev Cell. 2002 Oct;3(4):547–555. doi: 10.1016/s1534-5807(02)00288-5. [DOI] [PubMed] [Google Scholar]
  45. von Dassow G., Meir E., Munro E. M., Odell G. M. The segment polarity network is a robust developmental module. Nature. 2000 Jul 13;406(6792):188–192. doi: 10.1038/35018085. [DOI] [PubMed] [Google Scholar]

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