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Tenascin-R mediates activity-dependent recruitment of neuroblasts in the adult mouse forebrain

Nature Neuroscience volume 7, pages 347–356 (2004)Cite this article

Abstract

Neuroblasts arising in the adult forebrain that travel to the olfactory bulb use two modes of migration: tangentially, along the rostral migratory stream, and radially, in the core of the olfactory bulb where they start to ascend to the outer layers. Although the mechanisms of tangential migration have been extensively studied, the factors controlling radial migration remain unexplored. Here we report that the extracellular matrix glycoprotein tenascin-R, expressed in the adult mouse olfactory bulb, initiates both the detachment of neuroblasts from chains and their radial migration. Expression of tenascin-R is activity dependent, as it is markedly reduced by odor deprivation. Furthermore, grafting of tenascin-R-transfected cells into non-neurogenic regions reroutes migrating neuroblasts toward these regions. The identification of an extracellular microenvironment capable of directing migrating neuroblasts provides insights into the mechanisms regulating radial migration in the adult olfactory bulb and offers promising therapeutic venues for brain repair.

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Figure 1: Immunohistological detection of tenascin-R in the SVZ-OB pathway of adult mice.
Figure 2: Reduced density of newborn cells in the olfactory bulb of tenascin-R-deficient mice at 21 d after BrdU injection.
Figure 3: Normal proliferation in the SVZ and RMS of tenascin-R-deficient mice.
Figure 4: Normal chain organization and tangential migration of neuroblasts in tenascin-R-deficient mice.
Figure 5: Abnormal radial migration in the olfactory bulb of tenascin-R-deficient mutant mice.
Figure 6: Tenascin-R acts as a detachment signal for tangentially migrating neuroblasts.
Figure 7: Ectopic expression of tenascin-R reroutes migrating neuroblasts.
Figure 8: Activity-dependent expression of tenascin-R in the olfactory bulb.

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Acknowledgements

This work was supported by the Pasteur Institute, CNRS, The Annette Gruner-Schlumberger Foundation and grants from the French Ministry of Research and Education (ACI 'Biologie du Développement et Physiologie Intégrative' and GIS 'Infections à Prions') and the Gemeinnuetzige Hertie Stiftung. We are grateful to R. Grailhe and N. Mechawar for help with in situ hybridization, F.-A. Weltzien for help with quantitative PCR analysis, P. Roux at the 'Plate-form d'Imagerie Dynamique' of the Institut Pasteur for help with confocal microscopy, A. Cardona for help with the β-imager and M.-M. Gabellec for excellent technical assistance. We thank S. Freitag and F. Morellini for providing tenascin-R-deficient mice and M. Sibbe and M. Kutsche for the pcDNA3-TNR construct.

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Author notes

  1. Armen Saghatelyan and Antoine de Chevigny: These authors contributed equally to this study.

Authors and Affiliations

  1. Laboratory of Perception and Memory, CNRS URA 2182, Pasteur Institute, 25 rue du Dr. Roux, Paris, 75015, Cedex, France

    Armen Saghatelyan, Antoine de Chevigny & Pierre-Marie Lledo

  2. Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistrasse 52, Hamburg, D-20246, Germany

    Melitta Schachner

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Correspondence to Pierre-Marie Lledo.

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Supplementary information

Supplementary Fig. 1

Normal proliferation in the RMSOB of TNR-deficient mice. (a) PSA-NCAM (green) and BrdU (red) immunostaining in the RMSOBof control and TNR-deficient mice 2 h after BrdU injection. Note the very low numbers of BrdU+ cells (arrows) in the two groups. (b) Quantification of BrdU+ cells 2 h after BrdU injection and the proliferative marker Ki67+ cells in the RMSOB of control and TNR-deficient mice reveals no difference in the proliferation rates between the two genotypes. Data are presented as means ± s.e.m. Scale bars: a, 50 µm. (JPG 101 kb)

Supplementary Fig. 2

Reduced expression of TNR in the OB following odor deprivation. (a) Western blot analysis for TNR and NeuN expressions in the control (Ctrl) and occluded (Occl) bulbs following 20 days of sensory deprivation. Note the specific reduction of TNR expression in the odor-deprived bulb. (b) Effect of sensory deprivation on TNR mRNA and protein levels calculated by quantitative PCR and Western blotting 7 and 20 days following nostril occlusion, respectively. * and ** indicate significant differences of P < 0.05 and P < 0.01, respectively. Values in histograms are means ± s.e.m. (JPG 19 kb)

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Saghatelyan, A., de Chevigny, A., Schachner, M. et al. Tenascin-R mediates activity-dependent recruitment of neuroblasts in the adult mouse forebrain. Nat Neurosci 7, 347–356 (2004). https://doi.org/10.1038/nn1211

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