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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.

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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.

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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.

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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

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  1. Yunfu Sun
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Correspondence to Sylvia M Evans or Eric E Turner.

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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

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