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Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases

Nature Neuroscience volume 7, pages 136–144 (2004)Cite this article

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Abstract

Precise patterns of cell division and migration are crucial to transform the neuroepithelium of the embryonic forebrain into the adult cerebral cortex. Using time-lapse imaging of clonal cells in rat cortex over several generations, we show here that neurons are generated in two proliferative zones by distinct patterns of division. Neurons arise directly from radial glial cells in the ventricular zone (VZ) and indirectly from intermediate progenitor cells in the subventricular zone (SVZ). Furthermore, newborn neurons do not migrate directly to the cortex; instead, most exhibit four distinct phases of migration, including a phase of retrograde movement toward the ventricle before migration to the cortical plate. These findings provide a comprehensive and new view of the dynamics of cortical neurogenesis and migration.

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Figure 1: Radial glial cells divide asymmetrically in the ventricular zone (VZ), and intermediate progenitor cells divide symmetrically in the subventricular zone (SVZ).
Figure 2: Neocortical neurons exhibit four distinct phases of migration.
Figure 3: Intermediate progenitor cells divide in the subventricular zone (SVZ) to generate pairs of neurons.
Figure 5: Immunohistochemical and electrophysiological characterization of GFP+ double cell clones.
Figure 4: Immunohistochemical and electrophysiological characterization of GFP+ single-cell clones.
Figure 6: Radial glial cells undergo final divisions to generate translocating radial glia and intermediate progenitor cells.
Figure 7: Immunohistochemical and electrophysiological characterization of GFP+ translocating cells indicates transformation into astrocytes.

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  • 12 January 2004

    placed footnote in SGML where references to Supplementary videos 1-5 occur, and replaced actual legends online

Notes

  1. *Note: In the supplementary information that was posted at the time of the initial online publication of this article, the captions accompanying Supplementary Videos 1-5 online were incorrect. This error has been corrected for the HTML version of the captions online.

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Acknowledgements

We thank J. Goldman and members of the Kriegstein Lab for helpful comments on the manuscript, and W. Wong and J. Mirjahangir for technical assistance. This work was supported by National Institutes of Health grants (NS21223, NS38658 and NS35710) to A.R.K.

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Authors and Affiliations

  1. Department of Neurology, Columbia University College of Physicians & Surgeons, 630 W. 168th Street, New York, 10032, New York, USA

    Stephen C Noctor, Verónica Martínez-Cerdeño, Lidija Ivic & Arnold R Kriegstein

  2. Department of Pathology, Columbia University College of Physicians & Surgeons, 630 W. 168th Street, New York, 10032, New York, USA

    Arnold R Kriegstein

  3. Center for Neurobiology and Behavior, Columbia University College of Physicians & Surgeons, 630 W. 168th Street, New York, 10032, New York, USA

    Arnold R Kriegstein

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Supplementary information

Supplementary Video 1. Symmetric radial glial cell division.

Radial glial cells predominantly undergo asymmetric divisions, but also undergo symmetric progenitor divisions at the ventricular surface during late stages of neurogenesis. A radial glial cell is shown dividing with a vertical cleavage plane (t = 4 h). The resulting daughter cells have identical radial glial cell morphology and remain in the VZ for the length of the experiment (65 h, 45 h shown).* (MOV 2462 kb)

Supplementary Video 2. Neocortical neurons exhibit four distinct phases of migration.

Shown is a GFP+ multipolar single cell clone in the SVZ that had been labeled through an in utero retroviral injection one day prior to imaging. At the start of the time-lapse movie, the multipolar neuron is in the second phase of migration - migratory arrest in the SVZ. The neuron enters phase three of migration (retrograde movement toward the ventricle) and contacts the ventricular surface (t = 14 - 20 h). The neuron maintains contact with the ventricular surface, reverses polarity by developing a new leading process (t = 24 - 32 h), and migrates radially to the cortical plate.* (MOV 895 kb)

Supplementary Video 3. Intermediate precursor cells divide in the SVZ to generate pairs of neurons that also exhibit retrograde movement before migration to the cortical plate.

These paired cells progress through the phases of migration in tandem, and appear to interact as they migrate in close proximity to one another. The migrating cells can temporarily extend leading processes that reach the pia (t = 61 h), but then retract as the cells continue migrating.* (MOV 3046 kb)

Supplementary Video 4. Neocortical neurons leave a trailing axon in the ventricular zone during radial migration.

Many neocortical neurons that undergo retrograde migration to the ventricle leave a trailing process at the ventricular surface that remains in the VZ during radial migration. The leading process of the neuron during retrograde movement toward the ventricle becomes the trailing process as the neuron migrates radially to the cortical plate. The process remains in the VZ and lengthens by growing tangentially. The processes were morphologically identified as axons based on their thin uniform caliber and active growth cones.* (MOV 1792 kb)

Supplementary Video 5. Radial glial cells undergo final divisions to generate translocating radial glia and intermediate progenitor cells.

A radial glial cell is shown at the beginning of the time-lapse experiment. Its processes contact both the ventricular and pial surfaces of the cultured slice (200 μm width). The cortex grows during the experiment (700 μm width) beyond the initial field of view, but the radial glial cell maintains contact with the pial surface. The radial glial cell (red arrowhead) divides asymmetrically in the VZ (t = 23.5 h) to generate a presumed daughter neuron (white arrowhead) that undergoes retrograde movement toward the ventricle (t = 40.5 - 51.5 h) before migrating toward the cortical plate (t = 73 - 79 h) and moving deep into the tissue and out of the range of laser detection (t = 100 h). The radial glial cell divides a final time (t = 51.5 h). One daughter cell inherits the pial fiber and translocates toward the cortex (red arrowhead), while the other becomes multipolar (red arrow) and divides to generate a third cell (blue arrowhead) that can be seen at t = 112 h.* (MOV 849 kb)

*Note: In the supplementary information that was posted at the time of the initial online publication of this article, the captions accompanying Supplementary Videos 1-5 online were incorrect. This error has been corrected for the HTML version of the captions online.

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Noctor, S., Martínez-Cerdeño, V., Ivic, L. et al. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci 7, 136–144 (2004). https://doi.org/10.1038/nn1172

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