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Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain

Nature Neuroscience volume 9, pages 779–786 (2006)Cite this article

Abstract

The ability of the mature mammalian nervous system to continually produce neuronal precursors is of considerable importance, as manipulation of this process might one day permit the replacement of cells lost as a result of injury or disease. In mammals, the anterior subventricular zone (SVZa) region is one of the primary sites of adult neurogenesis. Here we show that doublecortin (DCX), a widely used marker for newly generated neurons, when deleted in mice results in a severe morphological defect in the rostral migratory stream and delayed neuronal migration that is independent of direction or responsiveness to Slit chemorepulsion. DCX is required for nuclear translocation and maintenance of bipolar morphology during migration of these cells. Our data identifies a critical function for DCX in the movement of newly generated neurons in the adult brain.

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Figure 1: Abnormally thickened RMS in Dcx−/y mutant mice.
Figure 2: Newly generated neurons do not migrate properly in Dcx−/y mice.
Figure 3: Defect in average velocity reflects 'stutter' in the initiation of migration in slices from Dcx−/y mice.
Figure 4: Decreased migration of neurons exiting the SVZa, due to a defect in nuclear translocation events.
Figure 5: DCX functions in suppression of branching of the primary neurite.

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Acknowledgements

The authors wish to thank A. Wynshaw-Boris (University of California, San Diego) and C. Walsh (Howard Hughes Medical Institute, Harvard Medical School, Boston) for Dcx knockout mice; M. Hatten and N. Heitz (Rockefeller University, New York; http://www.gensat.org; NIH NS02331), and J. Winkler and L. Aigner (University of Regensburg, Regensburg, Germany) for Dcx::EGFP mice; M. Ward and Y. Rao (Northwestern University, Chicago) for help with the SVZa explant culture system and for the Slit-producing stable HEK293T cell line; S. Tsukita (Japan Science and Technology Corporation, Kyoto, Japan) for the GFP-EB1 clone; N. Woods and R. Marr (Salk Institute, La Jolla, California) for lentiviral vectors and assistance; and J. Isaacson for electrophysiological measurements. This work was funded by the National Institute of Neurological Disorders and Stroke (R01 NS04387 and NS47101). We thank the Neurosciences Microscopy Shared Facility at the University of California, San Diego, for imaging support.

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Authors and Affiliations

  1. Department of Neurosciences, Neurogenetics Laboratory, University of California San Diego, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Hiroyuki Koizumi, Holden Higginbotham, Tiffany Poon, Teruyuki Tanaka, Brendan C Brinkman & Joseph G Gleeson

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Contributions

H.K. conducted the in vivo experiments. H.K., H.H. and T.P. conducted the in vitro experiments. H.H. prepared the virus and conditioned media. T.T. and B.C.B. provided technical and imaging expertise. All contributed to data analysis and manuscript preparation.

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Correspondence to Joseph G Gleeson.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

DCX expression in RMS and RMS morphological defects in Dcx null mice (PDF 714 kb)

Supplementary Fig. 2

No significant difference in numbers of calretinin (CR), parvalbumin (PV) or tyrosine hydroxylase (TH)-positive cells in the glomerular layer of Dcx−/y mice. (PDF 762 kb)

Supplementary Fig. 3

No apparent defect in responsiveness of Dcx Dcx−/y neurons to Slit chemorepulsion. (PDF 520 kb)

Supplementary Fig. 4

No apparent defects in centrosome structure and microtubule polymerization dynamics in Dcx−/y (PDF 294 kb)

Supplementary Video 1

Time-lapse imaging of neuronal movement from Dcx+/y; Dcx::EGFP. (MOV 1291 kb)

Supplementary Video 2

Time-lapse imaging of neuronal movement from Dcx−/y; Dcx::EGFP. (MOV 1582 kb)

Supplementary Video 3

Time-lapse DIC and fluorescent imaging of Dcx+/y; m⃗actin::Cetn2-EGFP isolated neurons in gel matrix. (MOV 1063 kb)

Supplementary Video 4

Time-lapse DIC and fluorescent imaging of Dcx−/y; m⃗actin::Cetn2-EGFP isolated neurons in gel matrix. (MOV 1022 kb)

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Koizumi, H., Higginbotham, H., Poon, T. et al. Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain. Nat Neurosci 9, 779–786 (2006). https://doi.org/10.1038/nn1704

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