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.

  • Article
  • Published:

A central role for Islet1 in sensory neuron development linking sensory and spinal gene regulatory programs

Nature Neuroscience volume 11, pages 1283–1293 (2008)Cite this article

Abstract

We used conditional knockout strategies in mice to determine the developmental events and gene expression program regulated by the LIM-homeodomain factor Islet1 in developing sensory neurons. Early development of the trigeminal and dorsal root ganglia was grossly normal in the absence of Islet1. From E12.5 onward, however, Isl1 mutant embryos showed a loss of the nociceptive markers TrkA and Runx1 and a near absence of cutaneous innervation. Proprioceptive neurons characterized by the expression of TrkC, Runx3 and Etv1 were relatively spared. Microarray analysis of Isl1 mutant ganglia revealed prolonged expression of developmental regulators that are normally restricted to early sensory neurogenesis and ectopic expression of transcription factors that are normally found in the CNS, but not in sensory ganglia. Later excision of Isl1 did not reactivate early genes, but resulted in decreased expression of transcripts related to specific sensory functions. Together these results establish a central role for Islet1 in the transition from sensory neurogenesis to subtype specification.

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: Defective development of the DRG and spinal nerves in Isl1 CKO mice.
Figure 2: Neurotrophin receptor expression in sensory ganglia lacking Islet1.
Figure 3: Expression of transcription factors regulating sensory subtype specification is altered in the DRG of Isl1 CKO embryos.
Figure 4: Islet1 regulates early and late programs of sensory gene expression.
Figure 5: Ectopic activation of spinal/hindbrain gene expression in Isl1 CKO sensory ganglia.
Figure 6: Late excision of Islet1 supports nociceptor survival but alters downstream gene expression.
Figure 7: Analysis of Isl1-induced knockout DRG at E18.5.

Similar content being viewed by others

References

  1. Ma, Q., Fode, C., Guillemot, F. & Anderson, D.J. Neurogenin1 and neurogenin2 control two distinct waves of neurogenesis in developing dorsal root ganglia. Genes Dev. 13, 1717–1728 (1999).

    Article  CAS  Google Scholar 

  2. Fode, C. et al. The bHLH protein Neurogenin2 is a determination factor for epibranchial placode–derived sensory neurons. Neuron 20, 483–494 (1998).

    Article  CAS  Google Scholar 

  3. Anderson, D.J. Lineages and transcription factors in the specification of vertebrate primary sensory neurons. Curr. Opin. Neurobiol. 9, 517–524 (1999).

    Article  CAS  Google Scholar 

  4. Eng, S.R. et al. Defects in sensory axon growth precede neuronal death in Brn3a-deficient mice. J. Neurosci. 21, 541–549 (2001).

    Article  CAS  Google Scholar 

  5. Eng, S.R., Lanier, J., Fedtsova, N. & Turner, E.E. Coordinated regulation of gene expression by Brn3a in developing sensory ganglia. Development 131, 3859–3870 (2004).

    Article  CAS  Google Scholar 

  6. Eng, S.R., Dykes, I.M., Lanier, J., Fedtsova, N. & Turner, E.E. POU-domain factor Brn3a regulates both distinct and common programs of gene expression in the spinal and trigeminal sensory ganglia. Neural Develop. 2, 3 (2007).

    Article  Google Scholar 

  7. Pfaff, S.L., Mendelsohn, M., Stewart, C.L., Edlund, T. & Jessell, T.M. Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron–dependent step in interneuron differentiation. Cell 84, 309–320 (1996).

    Article  CAS  Google Scholar 

  8. Cai, C.L. et al. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev. Cell 5, 877–889 (2003).

    Article  CAS  Google Scholar 

  9. Moretti, A. et al. Multipotent embryonic Isl1+ progenitor cells lead to cardiac, smooth muscle and endothelial cell diversification. Cell 127, 1151–1165 (2006).

    Article  CAS  Google Scholar 

  10. Sun, Y. et al. Islet 1 is expressed in distinct cardiovascular lineages, including pacemaker and coronary vascular cells. Dev. Biol. 304, 286–296 (2007).

    Article  CAS  Google Scholar 

  11. Woolf, C.J. & Ma, Q. Nociceptors—noxious stimulus detectors. Neuron 55, 353–364 (2007).

    Article  CAS  Google Scholar 

  12. Marmigere, F. & Ernfors, P. Specification and connectivity of neuronal subtypes in the sensory lineage. Nat. Rev. Neurosci. 8, 114–127 (2007).

    Article  CAS  Google Scholar 

  13. Chen, C-L. et al. Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain. Neuron 49, 365–377 (2006).

    Article  CAS  Google Scholar 

  14. Yoshikawa, M. et al. Runx1 selectively regulates cell fate specification and axonal projections of dorsal root ganglion neurons. Dev. Biol. 303, 663–674 (2007).

    Article  CAS  Google Scholar 

  15. Kramer, I. et al. A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification. Neuron 49, 379–393 (2006).

    Article  CAS  Google Scholar 

  16. Levanon, D. et al. The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons. EMBO J. 21, 3454–3463 (2002).

    Article  CAS  Google Scholar 

  17. Inoue, K. et al. Runx3 controls the axonal projection of proprioceptive dorsal root ganglion neurons. Nat. Neurosci. 5, 946–954 (2002).

    Article  CAS  Google Scholar 

  18. Quina, L.A. et al. Brn3a-expressing retinal ganglion cells project specifically to thalamocortical and collicular visual pathways. J. Neurosci. 25, 11595–11604 (2005).

    Article  CAS  Google Scholar 

  19. Lawson, S.N. & Biscoe, T.J. Development of mouse dorsal root ganglia: an autoradiographic and quantitative study. J. Neurocytol. 8, 265–274 (1979).

    Article  CAS  Google Scholar 

  20. Farinas, I., Wilkinson, G.A., Backus, C., Reichardt, L.F. & Patapoutian, A. Characterization of neurotrophin and Trk receptor functions in developing sensory ganglia: direct NT-3 activation of TrkB neurons in vivo. Neuron 21, 325–334 (1998).

    Article  CAS  Google Scholar 

  21. Fundin, B.T. et al. Differential dependency of cutaneous mechanoreceptors on neurotrophins, trk receptors, and P75 LNGFR. Dev. Biol. 190, 94–116 (1997).

    Article  CAS  Google Scholar 

  22. Luo, W. et al. A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons. Neuron 54, 739–754 (2007).

    Article  CAS  Google Scholar 

  23. Vellani, V. et al. Sensitization of transient receptor potential vanilloid 1 by the prokineticin receptor agonist Bv8. J. Neurosci. 26, 5109–5116 (2006).

    Article  CAS  Google Scholar 

  24. Gierl, M.S., Karoulias, N., Wende, H., Strehle, M. & Birchmeier, C. The zinc-finger factor Insm1 (IA-1) is essential for the development of pancreatic beta cells and intestinal endocrine cells. Genes Dev. 20, 2465–2478 (2006).

    Article  CAS  Google Scholar 

  25. Laugwitz, K.L. et al. Postnatal Isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433, 647–653 (2005).

    Article  CAS  Google Scholar 

  26. Fedtsova, N.G. & Turner, E.E. Brn-3.0 Expression identifies early post-mitotic CNS neurons and sensory neural precursors. Mech. Dev. 53, 291–304 (1995).

    Article  CAS  Google Scholar 

  27. Lanier, J., Quina, L.A., Eng, S.R., Cox, E. & Turner, E.E. Brn3a target gene recognition in embryonic sensory neurons. Dev. Biol. 302, 703–716 (2007).

    Article  CAS  Google Scholar 

  28. Breslin, M.B., Zhu, M. & Lan, M.S. NeuroD1/E47 regulates the E-box element of a novel zinc finger transcription factor, IA-1, in developing nervous system. J. Biol. Chem. 278, 38991–38997 (2003).

    Article  CAS  Google Scholar 

  29. Marmigere, F. et al. The Runx1/AML1 transcription factor selectively regulates development and survival of TrkA nociceptive sensory neurons. Nat. Neurosci. 9, 180–187 (2006).

    Article  CAS  Google Scholar 

  30. Huang, E.J. et al. POU domain factor Brn-3a controls the differentiation and survival of trigeminal neurons by regulating Trk receptor expression. Development 126, 2869–2882 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. McEvilly, R.J. et al. Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons. Nature 384, 574–577 (1996).

    Article  CAS  Google Scholar 

  32. Ichikawa, H., Mo, Z., Xiang, M. & Sugimoto, T. Effect of Brn-3a deficiency on parvalbumin-immunoreactive primary sensory neurons in the dorsal root ganglion. Brain Res. Dev. Brain Res. 150, 41–45 (2004).

    Article  CAS  Google Scholar 

  33. Paratore, C., Brugnoli, G., Lee, H.Y., Suter, U. & Sommer, L. The role of the Ets domain transcription factor Erm in modulating differentiation of neural crest stem cells. Dev. Biol. 250, 168–180 (2002).

    Article  CAS  Google Scholar 

  34. Chotteau-Lelievre, A., Desbiens, X., Pelczar, H., Defossez, P.A. & de Launoit, Y. Differential expression patterns of the PEA3 group transcription factors through murine embryonic development. Oncogene 15, 937–952 (1997).

    Article  CAS  Google Scholar 

  35. Hippenmeyer, S. et al. A developmental switch in the response of DRG neurons to ETS transcription factor signaling. PLoS Biol. 3, e159 (2005).

    Article  Google Scholar 

  36. Lei, L., Zhou, J., Lin, L. & Parada, L.F. Brn3a and Klf7 cooperate to control TrkA expression in sensory neurons. Dev. Biol. 300, 758–769 (2006).

    Article  CAS  Google Scholar 

  37. Chen, Z.F. et al. The paired homeodomain protein DRG11 is required for the projection of cutaneous sensory afferent fibers to the dorsal spinal cord. Neuron 31, 59–73 (2001).

    Article  CAS  Google Scholar 

  38. Rebelo, S., Chen, Z.F., Anderson, D.J. & Lima, D. Involvement of DRG11 in the development of the primary afferent nociceptive system. Mol. Cell. Neurosci. 33, 236–246 (2006).

    Article  CAS  Google Scholar 

  39. Kania, A., Johnson, R.L. & Jessell, T.M. Coordinate roles for LIM homeobox genes in directing the dorsoventral trajectory of motor axons in the vertebrate limb. Cell 102, 161–173 (2000).

    Article  CAS  Google Scholar 

  40. Kania, A. & Jessell, T.M. Topographic motor projections in the limb imposed by LIM homeodomain protein regulation of ephrin-A:EphA interactions. Neuron 38, 581–596 (2003).

    Article  CAS  Google Scholar 

  41. Mizuhara, E., Nakatani, T., Minaki, Y., Sakamoto, Y. & Ono, Y. Corl1, a novel neuronal lineage-specific transcriptional co-repressor for the homeodomain transcription factor Lbx1. J. Biol. Chem. 280, 3645–3655 (2005).

    Article  CAS  Google Scholar 

  42. Gross, M.K., Dottori, M. & Goulding, M. Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord. Neuron 34, 535–549 (2002).

    Article  CAS  Google Scholar 

  43. Muller, T. et al. The homeodomain factor lbx1 distinguishes two major programs of neuronal differentiation in the dorsal spinal cord. Neuron 34, 551–562 (2002).

    Article  CAS  Google Scholar 

  44. Zhou, Q. & Anderson, D.J. The bHLH transcription factors OLIG2 and OLIG1 couple neuronal and glial subtype specification. Cell 109, 61–73 (2002).

    Article  CAS  Google Scholar 

  45. Novitch, B.G., Chen, A.I. & Jessell, T.M. Coordinate regulation of motor neuron subtype identity and pan-neuronal properties by the bHLH repressor Olig2. Neuron 31, 773–789 (2001).

    Article  CAS  Google Scholar 

  46. Lee, S.K., Lee, B., Ruiz, E.C. & Pfaff, S.L. Olig2 and Ngn2 function in opposition to modulate gene expression in motor neuron progenitor cells. Genes Dev. 19, 282–294 (2005).

    Article  CAS  Google Scholar 

  47. Reik, W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447, 425–432 (2007).

    Article  CAS  Google Scholar 

  48. Ahlgren, U., Pfaff, S.L., Jessell, T.M., Edlund, T. & Edlund, H. Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. Nature 385, 257–260 (1997).

    Article  CAS  Google Scholar 

  49. Naya, F.J. et al. Diabetes, defective pancreatic morphogenesis and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev. 11, 2323–2334 (1997).

    Article  CAS  Google Scholar 

  50. Liu, W.D., Wang, H.W., Muguira, M., Breslin, M.B. & Lan, M.S. INSM1 functions as a transcriptional repressor of the neuroD/beta2 gene through the recruitment of cyclin D1 and histone deacetylases. Biochem. J. 397, 169–177 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank T. Jessell, S. Arber, L. Reichardt, M. Wegner, D. Lima and S. Pfaff for antibodies, and Q. Ma and J. Johnson for in situ hybridization probes (Methods). We would also like to thank N. Webster and L. Shireen of the University of California San Diego/Veterans Affairs Microarray Core for assistance with microarray technology, and G.C. Parico and A. Jackson for technical assistance. Mouse monoclonal antibodies were obtained from the Developmental Studies Hybridoma Bank, maintained under contract NO1-HD23144 from the US National Institute of Child Health and Human Development. This work was supported in part by Department of Veterans Affairs MERIT funding and US National Institutes of Health awards HD33442 and MH065496 to E.E.T. and HL074066 to S.M.E. E.E.T. is a National Alliance for Research on Schizophrenia and Depression Investigator.

Author information

Authors and Affiliations

  1. Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, 93093, California, USA

    Yunfu Sun, Xingqun Liang & Sylvia M Evans

  2. School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, 93093, California, USA

    Yunfu Sun & Sylvia M Evans

  3. Department of Psychiatry, University of California, San Diego, 9500 Gilman Drive, La Jolla, 93093, California, USA

    Iain M Dykes, S Raisa Eng & Eric E Turner

  4. VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, 92161, California, USA

    Eric E Turner

Authors
  1. Yunfu Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Iain M Dykes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xingqun Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Raisa Eng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sylvia M Evans
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eric E Turner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sylvia M Evans or Eric E Turner.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1–3 and Supplementary Methods (PDF 1031 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sun, Y., Dykes, I., Liang, X. et al. A central role for Islet1 in sensory neuron development linking sensory and spinal gene regulatory programs. Nat Neurosci 11, 1283–1293 (2008). https://doi.org/10.1038/nn.2209

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2209

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