Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Sensory ataxia and muscle spindle agenesis in mice lacking the transcription factor Egr3

Nature Genetics volume 20, pages 87–91 (1998)Cite this article

Abstract

Muscle spindles are skeletal muscle sensory organs that provide axial and limb position information (proprioception) to the central nervous system. Spindles consist of encapsulated muscle fibers (intrafusal fibers) that are innervated by specialized motor and sensory axons. Although the molecular mechanisms involved in spindle ontogeny are poorly understood, the innervation of a subset of developing myotubes (type I) by peripheral sensory afferents (group Ia) is a critical event for inducing intrafusal fiber differentiation and subsequent spindle formation1,2,3. The Egr family of zinc-finger transcription factors, whose members include Egr1 (NGFI-A), Egr2 (Krox-20), Egr3 and Egr4 (NGFI-C), are thought to regulate critical genetic programs involved in cellular growth and differentiation (refs 4, 5, 6, 7, 8 and W.G.T. et al., manuscript submitted). Mice deficient in Egr3 were generated by gene targeting and had gait ataxia, increased frequency of perinatal mortality, scoliosis, resting tremors and ptosis. Although extrafusal skeletal muscle fibers appeared normal, Egr3-deficient animals lacked muscle spindles, a finding that is consistent with their profound gait ataxia. Egr3 was highly expressed in developing muscle spindles, but not in Ia afferent neurons or their terminals during developmental periods that coincided with the induction of spindle morphogenesis by sensory afferent axons. These results indicate that type I myotubes are dependent upon Egr3-mediated transcription for proper spindle development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Targeted mutation of Egr3.
Figure 2: Slow-tonic MHC and acid-stable ATPase stains in adult mouse skeletal muscle.
Figure 3: Morphometric analyses of proprioceptive neurons, group Ia afferents and gamma motor efferents.
Figure 4: Muscle spindle morphogenesis and central group Ia afferents in wild-type and Egr3-deficient mice.
Figure 5: Peripheral group Ia-like afferents in wild-type and Egr3-deficient three-day-old mouse skeletal muscle.
Figure 6: Egr3 expression in developing wild-type muscle spindles.

Similar content being viewed by others

References

  1. Kucera, J., Fan, G., Jaenisch, R., Linnarsson, S. & Ernfors, P. Dependence of developing group Ia afferents on neurotrophin-3. J. Comp. Neurol. 363, 307–320 (1995).

    Article  CAS  Google Scholar 

  2. Kucera, J. & Walro, J.M. Origin of intrafusal fibers from a subset of primary myotubes in the rat. Anat. Embryol. (Berl) 192, 149–158 (1995).

    CAS  Google Scholar 

  3. Zelená, J. The morphogenic influences of innervation on the ontogenic development of muscle spindles. J. Embryol. Exp. Morphol. 5, 283–292 (1957).

    Google Scholar 

  4. Lee, S.L. et al. Luteinizing hormone deficiency and female infertility in mice lacking the transcription factor NGFI-A (Egr-1). Science 273, 1219–1221 (1996).

    Article  CAS  Google Scholar 

  5. Nguyen, H.Q., Hoffman-Liebermann, B. & Liebermann, D.A. The zinc finger transcription factor Egr-1 is essential for and restricts differentiation along the macrophage lineage. Cell 72, 197–209 (1993).

    Article  CAS  Google Scholar 

  6. Sukhatme, V.P. et al. A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization. Cell 53, 37–43 (1988).

    Article  CAS  Google Scholar 

  7. Sham, M.H. et al. The zinc finger gene Krox20 regulates HoxB2 (Hox2.8) during hindbrain segmentation. Cell 72, 183–196 (1993).

    Article  CAS  Google Scholar 

  8. Swiatek, P.J. & Gridley, T. Perinatal lethality and defects in hindbrain development in mice homozygous for a targeted mutation of the zinc finger gene Krox20. Genes Dev. 7, 2071–2084 (1993).

    Article  CAS  Google Scholar 

  9. Kucera, J. & Walro, J.M. Superfluousness of motor innervation for the formation of muscle spindles in neonatal rats. Anat. Embryol. (Berl) 186, 301–309 (1992).

    Article  CAS  Google Scholar 

  10. Topilko, P. et al. Krox-20 controls myelination in the peripheral nervous system. Nature 371, 796–799 (1994).

    Article  CAS  Google Scholar 

  11. Celio, M.R. Calbindin D-28k and parvalbumin in the rat nervous system. Neuroscience 35, 375–475 (1990).

    Article  CAS  Google Scholar 

  12. Copray, J.C., Mantingh-Otter, I.J. & Brouwer, N. Expression of calcium-binding proteins in the neurotrophin-3-dependent subpopulation of rat embryonic dorsal root ganglion cells in culture. Brain Res. Dev. Brain Res. 81, 57–65 (1994).

    Article  CAS  Google Scholar 

  13. Duchen, L.W. & Scaravilli, F. The structure and composition of peripheral nerves and nerve roots in the Sprawling mouse. J. Anat. 123, 763–775 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kawamura, Y., Okazaki, H., O’Brien, P.C. & Dych, P.J. Lumbar motoneurons of man: I) number and diameter histogram of alpha and gamma axons of ventral root. J. Neuropathol. Exp. Neurol. 36, 853–860 (1977).

    Article  CAS  Google Scholar 

  15. Yamagata, K. et al. Egr3/Pilot, a zinc finger transcription factor, is rapidly regulated by activity in brain neurons and colocalizes with Eg1/zif268. Learning and Memory 1, 140–152 (1994).

    CAS  PubMed  Google Scholar 

  16. Morris, M.E., Viswanathan, N., Kuhlman, S., Davis, F.C. & Weitz, C.J. A screen for genes induced in the suprachiasmatic nucleus by light. Science 279, 1544–1547 (1998).

    Article  CAS  Google Scholar 

  17. Ernfors, P., Lee, K.F., Kucera, J. & Jaenisch, R. Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents. Cell 77, 503–512 (1994).

    Article  CAS  Google Scholar 

  18. Klein, R. et al. Disruption of the neurotrophin-3 receptor gene trkC eliminates la muscle afferents and results in abnormal movements. Nature 368, 249–251 (1994).

    Article  CAS  Google Scholar 

  19. Farinas, I., Jones, K.R., Backus, C., Wang, X.Y. & Reichardt, L.F. Severe sensory and sympathetic deficits in mice lacking neurotrophin-3. Nature 369, 658–661 (1994).

    Article  CAS  Google Scholar 

  20. Tessarollo, L., Vogel, K.S., Palko, M.E., Reid, S.W. & Parada, L.F. Targeted mutation in the neurotrophin-3 gene results in loss of muscle sensory neurons. Proc. Natl Acad. Sci. USA 91, 11844–11848 (1994).

    Article  CAS  Google Scholar 

  21. Ringstedt, T., Kucera, J., Lendahl, U., Ernfors, P. & Ibanez, C.F. Limb proprioceptive deficits without neuronal loss in transgenic mice overexpressing neurotrophin-3 in the developing nervous system. Development 124, 2603–2613 (1997).

    CAS  PubMed  Google Scholar 

  22. McMahon, A.P. & Bradley, A. The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell 62, 1073–1085 (1990).

    Article  CAS  Google Scholar 

  23. O’Donovan, K.J., Wilkens, E.P. & Baraban, J.M. Sequential expression of Egr-1 and Egr-3 in hippocampal granule cells following electroconvulsive stimulation. J. Neurochem. 70, 1241–1248 (1998).

    Article  Google Scholar 

  24. Mithani, S., Atmadja, S., Baimbridge, K.G. & Fibiger, H.C. Neuroleptic-induced oral dyskinesias: effects of progabide and lack of correlation with regional changes in glutamic acid decarboxylase and choline acetyltransferase activities. Psychopharmacology (Berl) 93, 94–100 (1987).

    Article  CAS  Google Scholar 

  25. Crow, M.T. & Stockdale, F.E. Myosin expression and specialization among the earliest muscle fibers of the developing avian limb. Dev. Biol. 113, 238–254 (1986).

    Article  CAS  Google Scholar 

  26. Brooke, M.H. & Kaiser, K.K. Three “myosin adenosine triphosphatase” systems: the nature of their pH lability and sulfhydryl dependence. J. Histochem. Cytochem. 18, 670–672 (1970).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We greatly appreciate technical assistance from L. Cabalka Tourtellotte, G. Gavrilina, T. Gorodinsky, C. Bollinger and L. Roberts. We thank E. Johnson, J. Lichtman, J. Sanes and B. Snider for their comments and suggestions during the preparation of this manuscript. The antibodies to Parvalbumin (R301), slow-tonic myosin heavy chain (S46) and Egr3 were generous gifts from K. Baimbridge, F. Stockdale and J. Baraban, respectively. A. Pestronk generously provided the ATPase histochemistry protocols. This work was supported by MH1426 (W.G.T.) and CA13730 (J.M.).

Author information

Authors and Affiliations

  1. The Department of Pathology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Warren G. Tourtellotte & Jeffrey Milbrandt

  2. Division of Neuropathology, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Warren G. Tourtellotte

  3. Division of Laboratory Medicine, Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Jeffrey Milbrandt

Authors
  1. Warren G. Tourtellotte
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeffrey Milbrandt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey Milbrandt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tourtellotte, W., Milbrandt, J. Sensory ataxia and muscle spindle agenesis in mice lacking the transcription factor Egr3. Nat Genet 20, 87–91 (1998). https://doi.org/10.1038/1757

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/1757

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing