, Volume 112, Issue 8, pp 398–409 | Cite as

Targeting SMN to Cajal bodies and nuclear gems during neuritogenesis

  • Joaquin Navascues
  • Maria T. Berciano
  • Karen E. Tucker
  • Miguel LafargaEmail author
  • A. Gregory MateraEmail author
Research Article


Neurite outgrowth is a central feature of neuronal differentiation. PC12 cells are a good model system for studying the peripheral nervous system and the outgrowth of neurites. In addition to the dramatic changes observed in the cytoplasm, neuronal differentiation is also accompanied by striking changes in nuclear morphology. The large and sustained increase in nuclear transcription during neuronal differentiation requires synthesis of a large number of factors involved in pre-mRNA processing. We show that the number and composition of the nuclear subdomains called Cajal bodies and gems changes during the course of N-ras-induced neuritogenesis in the PC12-derived cell line UR61. The Cajal bodies found in undifferentiated cells are largely devoid of the survival of motor neurons (SMN) protein product. As cells shift to a differentiated state, SMN is not only globally upregulated, but is progressively recruited to Cajal bodies. Additional SMN foci (also known as Gemini bodies, gems) can also be detected. Using dual-immunogold labeling electron microscopy and mouse embryonic fibroblasts lacking the coilin protein, we show that gems clearly represent a distinct category of nuclear body.


Tyrosine Hydroxylase Nuclear Body Dexamethasone Treatment Cajal Body Tyrosine Hydroxylase Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported by grants from the following institutions: Centro de Investigación de Enfermedades Neurológicas (CIEN), Instituto de Salud Carlos III (Madrid, Spain); Dirección General de Investigacion of Spain (BFI2002-0454); the National Institutes of Health, USA (R01-NS41617 and R01-GM53034) and the Muscular Dystrophy Association, USA (RG 3290).


  1. Bar-Sagi D, Feramisco JR (1985) Microinjection of the ras oncogene protein into PC12 cells induces morphological differentiation. Cell 42:841–848PubMedGoogle Scholar
  2. Bohmann K, Ferreira JA, Lamond AI (1995) Mutational analysis of p80 coilin indicates a functional interaction between coiled bodies and the nucleolus. J Cell Biol 131:817–831PubMedGoogle Scholar
  3. Boisvert FM, Cote J, Boulanger MC, Cleroux P, Bachand F, Autexier C, Richard S (2002) Symmetrical dimethylarginine methylation is required for the localization of SMN in Cajal bodies and pre-mRNA splicing. J Cell Biol 159:957–969CrossRefPubMedGoogle Scholar
  4. Cajal SR (1910) El núcleo de las células piramidales del cerebro humano y de algunos mamíferos. Trab Lab Invest Biol 8:27–62Google Scholar
  5. Carvalho T, Almeida F, Calapez A, Lafarga M, Berciano MT, Carmo-Fonseca M (1999) The spinal muscular atrophy disease gene product, SMN: a link between snRNP biogenesis and the Cajal (coiled) body. J Cell Biol 147:715–727PubMedGoogle Scholar
  6. Chao MV, Hempstead BL (1995) p75 and Trk: a two-receptor system. Trends Neurosci 18:321–326Google Scholar
  7. D’Arcangelo G, Halegoua S (1993) A branched signaling pathway for nerve growth factor is revealed by Src-, Ras-, and Raf-mediated gene inductions. Mol Cell Biol 13:3146–3155PubMedGoogle Scholar
  8. Gall JG (2000) Cajal bodies: the first 100 years. Annu Rev Cell Dev Biol 16:273–300PubMedGoogle Scholar
  9. Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 73:2424–2428PubMedGoogle Scholar
  10. Guerrero I, Pellicer A, Burstein DE (1988) Dissociation of c-Fos from ODC expression and neuronal differentiation in a PC12 subline stably transfected with an inducible N-Ras oncogene. Biochem Biophys Res 150:1185–1192Google Scholar
  11. Hagerty T, Morgan WW, Elango N, Strong R (2001) Identification of a glucocorticoid-responsive element in the promoter region of the mouse tyrosine hydroxylase gene. J Neurochem 76:825–834CrossRefPubMedGoogle Scholar
  12. Hebert MD, Shpargel KB, Ospina JK, Tucker KE, Matera AG (2002) Coilin methylation regulates nuclear body formation. Dev Cell 3:329–337PubMedGoogle Scholar
  13. Jady BE, Darzacq X, Tucker KE, Matera AG, Bertrand E, Kiss T (2003) Modification of Sm small nuclear RNAs occurs in the nucleoplasmic Cajal body following import from the cytoplasm. EMBO J 22:4283–4293CrossRefPubMedGoogle Scholar
  14. Jansen RP, Hurt EC, Kern H, Lehtonen H, Carmo-Fonseca M (1991) Evolutionary conservation of the human nucleolar protein fibrillarin and its functional expression in yeast. J Cell Biol 113:715–729PubMedGoogle Scholar
  15. Kandel ER, Schwartz JH, Jessell TM (2000) Principles of neural science. McGraw-Hill Company, New YorkGoogle Scholar
  16. Lafarga M, Hervas JP, Santa-Cruz MC, Villegas J, Crespo D (1983) The “accessory body” of Cajal in the neuronal nucleus. A light and electron microscopic approach. Anat Embryol 166:19–30PubMedGoogle Scholar
  17. Lafarga M, Andres MA, Berciano MT, Maquiera E (1991) Organization of nucleoli and nuclear bodies in osmotically stimulated supraoptic neurons of the rat. J Comp Neurol 308:329–339PubMedGoogle Scholar
  18. Lafarga M, Berciano MT, Garcia-Segura LM, Andres MA, Carmo-Fonseca M (1998) Acute osmotic/stress stimuli induce a transient decrease of transcriptional activity in the neurosecretory neurons of supraoptic nuclei. J Neurocytol 27:205–217PubMedGoogle Scholar
  19. Liu Q, Dreyfuss G (1996) A novel nuclear structure containing the survival of motor neurons protein. EMBO J 15:3555–3565PubMedGoogle Scholar
  20. Liu Q, Fischer U, Wang F, Dreyfuss G (1997) The spinal muscular atrophy disease gene product, SMN, and its associated protin SIP1 are in a complex with spliceosomal snRNP proteins. Cell 90:1013–1021PubMedGoogle Scholar
  21. Meier UT, Blobel G (1992) Nopp 140 shuttles on tracks between nucleolus and cytoplasm. Cell 70:127-138PubMedGoogle Scholar
  22. Malatesta M, Scassellati C, Meister G, Plottner O, Buhler D, Sowa G, Martin TE, Keidel E, Fischer U, Fakan S (2004) Ultrastructural characterisation of a nuclear domain highly enriched in survival of motor neuron (SMN) protein. Exp Cell Res 292:312–321CrossRefPubMedGoogle Scholar
  23. Noda M, Ko M, Ogura A, Liu DG, Amano T, Tacano T, Ikawa Y (1985) Sarcoma viruses carrying ras oncogenes induce differentiation-associated properties in a neuronal cell line. Nature 318:73–75PubMedGoogle Scholar
  24. Pena E, Berciano MT, Fernandez R, Ojeda JL, Lafarga M (2001) Neuronal body size correlates with the number of nucleoli and Cajal bodies, and with the organization of the splicing machinery in rat trigeminal ganglion neurons. J Comp Neurol 430:250–263PubMedGoogle Scholar
  25. Peters A, Palay SL, Webster H de F (1991) The fine structure of the nervous system. Neurons and their supporting cells. Oxford University Press, New YorkGoogle Scholar
  26. Santama N, Dotti CG, Lamond AI (1996) Neuronal differentiation in the rat hippocampus involves a stage-specific reorganization of subnuclear structure both in vivo and in vitro. Eur J Neurosci 8:892–905PubMedGoogle Scholar
  27. Schul W, Groenhaut B, Koberna K, Takagaki Y, Jenny A, Manders EM, Raska I, van Driel R, de Jong L (1996) The RNA 3′ cleavage factors CstF 64 kDa and CPSF 100 kDa are concentrated in nuclear domains closely associated with coiled bodies and newly synthesized RNA. EMBO J 15:2883–2892PubMedGoogle Scholar
  28. Shpargel KB, Ospina JK, Tucker KE, Matera AG, Hebert MD (2003) Control of Cajal body number is mediated by the coilin C-terminus. J Cell Sci 14:9–16Google Scholar
  29. Sleeman JE, Trinkle-Mulcahy L, Prescott AR, Ogg SC, Lamond AI (2003) Cajal body proteins SMN and coilin show differential dynamic behaviour in vivo. J Cell Sci 116:2039–2050CrossRefPubMedGoogle Scholar
  30. Tischer AS, Greene LA (1978) Morphologic and cytochemical properties of a clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Lab Invest 39:77–89PubMedGoogle Scholar
  31. Tucker KE, Berciano MT, Jacobs EY, LePage DF, Shpargel KB, Rossire J, Chan EKL, Lafarga M, Colon RA, Matera AG (2001) Residual Cajal bodies in coilin knockout mice fail to recruit Sm snRNPs and SMN, the spinal muscular atrophy gene product. J Cell Biol 154:293–307CrossRefPubMedGoogle Scholar
  32. Vaudry D, Stork JS, Lazarovici P, Eiden LE (2002) Signaling pathways for PC12 cell differentiation: Making the right connections. Science 296:1648–1649CrossRefPubMedGoogle Scholar
  33. Verheggen C, Lafontaine DL, Samarsky D, Mouaikel J, Blanchard JM, Bordonne R, Bertrand E (2002) Mammalian and yeast U3 snoRNPs are matured in specific and related nuclear compartments. EMBO J 21:2736–2756PubMedGoogle Scholar
  34. Young PJ, Le TT, thi Man N, Burghes AH, Morris GE (2000) The relationship between SMN, the spinal muscular atrophy protein, and nuclear coiled bodies in differentiated tissues and cultured cells. Exp Cell Res 256:365–374CrossRefPubMedGoogle Scholar
  35. Young PJ, Le TT, Dunckley M, thi Man N, Burghes AH, Morris GE (2001) Nuclear gems and Cajal (Coiled) bodies in fetal tissues: Nucleolar distribution of the spinal muscular atrophy protein, SMN. Exp Cell Res 265:252–261CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Department of Anatomy and Cell Biology, Biomedicine Unit, CSICUniversity of CantabriaSantanderSpain
  2. 2.Department of GeneticsCase Western Reserve UniversityClevelandUSA

Personalised recommendations