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Induction of neurogenesis in the neocortex of adult mice

Nature volume 405, pages 951–955 (2000)Cite this article

Abstract

Neurogenesis normally only occurs in limited areas of the adult mammalian brain—the hippocampus1, olfactory bulb2,3,4 and epithelium5, and at low levels in some regions of macaque cortex6. Here we show that endogenous neural precursors can be induced in situ to differentiate into mature neurons, in regions of adult mammalian neocortex that do not normally undergo any neurogenesis. This differentiation occurs in a layer- and region-specific manner, and the neurons can re-form appropriate corticothalamic connections. We induced synchronous apoptotic degeneration7,8 of corticothalamic neurons in layer VI of anterior cortex of adult mice and examined the fates of dividing cells within cortex, using markers for DNA replication (5-bromodeoxyuridine; BrdU) and progressive neuronal differentiation. Newly made, BrdU-positive cells expressed NeuN, a mature neuronal marker, in regions of cortex undergoing targeted neuronal death and survived for at least 28 weeks. Subsets of BrdU+ precursors expressed Doublecortin, a protein found exclusively in migrating neurons9,10, and Hu, an early neuronal marker11,12. Retrograde labelling from thalamus demonstrated that BrdU+ neurons can form long-distance corticothalamic connections. Our results indicate that neuronal replacement therapies for neurodegenerative disease and CNS injury may be possible through manipulation of endogenous neural precursors in situ.

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Figure 1: Newly generated BrdU+ cells can be induced to differentiate into neurons, in regions of cortex undergoing targeted apoptotic degeneration of corticothalamic neurons.
Figure 2: New cells express the migratory neuronal marker Doublecortin (Dcx) two weeks after induction of apoptosis.
Figure 3: Newly generated BrdU+ cells express the early neuronal marker Hu in experimental cortex.
Figure 4: Newly generated BrdU+ neurons in experimental cortex extend long-distance projections to thalamus.

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Acknowledgements

We thank J. Gleeson, S. Goldman, M. Marusich, C. Walsh, and P. Follett for reagents; M. Christian and C. Tai for technical assistance; L. Catapano, P. Follett, R. Fricker, M. Gates, and J. Gleeson for discussions; and L. Benowitz, M. Greenberg, L. Kunkel, and C. Walsh for critical reading. This work was supported by grants from the NIH (J.D.M.), Alzheimer's Association (J.D.M.), Human Frontiers Science Program (J.D.M.), an NIH predoctoral training grant (S.S.M.), and a postdoctoral fellowship from the Canadian MRC (B.R.L.).

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  1. Blair R. Leavitt

    Present address: Center for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada

  2. Correspondence and requests for materials should be addressed to J.D.M.

Authors and Affiliations

  1. Division of Neuroscience, Children's Hospital,

    Sanjay S. Magavi, Blair R. Leavitt & Jeffrey D. Macklis

  2. Department of Neurology and Program in Neuroscience, Harvard Medical School, Enders 350, 320 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Sanjay S. Magavi, Blair R. Leavitt & Jeffrey D. Macklis

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Correspondence to Jeffrey D. Macklis.

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Magavi, S., Leavitt, B. & Macklis, J. Induction of neurogenesis in the neocortex of adult mice. Nature 405, 951–955 (2000). https://doi.org/10.1038/35016083

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