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DOCK7 interacts with TACC3 to regulate interkinetic nuclear migration and cortical neurogenesis

Nature Neuroscience volume 15, pages 1201–1210 (2012)Cite this article

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Abstract

Neurogenesis in the developing neocortex relies on the ability of radial glial progenitor cells (RGCs) to switch from proliferative to differentiative neuron-generating divisions, but the molecular mechanisms that control this switch in a correct temporal manner are not well understood. Here, we show that DOCK7, a member of the DOCK180 family of proteins, regulates RGC proliferation versus differentiation. Silencing of DOCK7 in RGCs of developing mouse embryos impedes neuronal differentiation and maintains cells as cycling progenitors. In contrast, DOCK7 overexpression promotes RGC differentiation to basal progenitors and neurons. We further present evidence that DOCK7 influences neurogenesis by controlling apically directed interkinetic nuclear migration of RGCs. DOCK7 exerts its effects by antagonizing the microtubule growth-promoting function of the centrosome-associated protein TACC3. Thus, DOCK7 interaction with TACC3 controls interkinetic nuclear migration and the genesis of neurons from RGCs during cortical development.

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Figure 1: Distribution and localization of DOCK7 in the developing mouse cortex.
Figure 2: DOCK7 modulates the VZ progenitor pool size.
Figure 3: DOCK7 is required for the transition of RGCs to basal progenitors and genesis of neurons.
Figure 4: DOCK7 controls bl-to-ap INM of RGCs.
Figure 5: Altered DOCK7 expression affects apically directed INM of RGCs in acute cortical slices.
Figure 6: DOCK7 interacts with TACC3.
Figure 7: DOCK7 antagonizes TACC3 function during cortical neurogenesis.
Figure 8: DOCK7 antagonizes microtubule growth–promoting or microtubule-stabilizing function of TACC3.

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Acknowledgements

We thank members of the Van Aelst laboratory, E.-E. Govek and J. Skowronski for discussions and/or critical reading of the manuscript. We thank N. Gray and J.W. Tsai for technical advice regarding the in utero electroporation procedure and K. John for yeast two-hybrid screening. We also thank F. Matsuzaki (RIKEN Center for Developmental Biology) and L.-H. Tsai (Massachusetts Institute of Technology) for reagents. This work was supported by US National Institutes of Health grant MH082808 and a New York STARR consortium grant to L.V.A. C.-L.W. is supported by US National Institutes of Health research training grant T32 CA 148056-1.

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  1. Yu-Ting Yang and Chia-Lin Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA

    Yu-Ting Yang, Chia-Lin Wang & Linda Van Aelst

  2. Molecular and Cellular Biology Program, Stony Brook University, Stony Brook, New York, USA

    Yu-Ting Yang

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Y.-T.Y., C.-L.W. and L.V.A. conceived and designed the project. Y.-T.Y. and C.-L.W. performed all the experiments and prepared the figures. L.V.A. wrote the manuscript.

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Correspondence to Linda Van Aelst.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12, Supplementary Data (PDF 6851 kb)

Supplementary Video 1

Example of a control vector expressing RGC (top left cell) undergoing bl-to-ap INM in VZ of neocortex. Time-lapse imaging was carried out on acute cortical slices 2 d after in utero electroporation of plasmids expressing empty control vector, and EGFP (green) and mKO2-F (red) fluorescent markers (at E15.5). Images acquired over an 8-h time period are shown; time (in min) is indicated on the top. Note: the cell body of the RGC migrates steadily toward the ventricle. After about 5 h, it reaches the ventricular (apical) surface, and the cell subsequently divides at the ventricular surface. (AVI 230 kb)

Supplementary Video 2

Example 1 of a DOCK7-overexpressing RGC (cell in the middle) undergoing bl-to-ap INM in VZ of neocortex. Time-lapse imaging was carried out on acute cortical slices 2 d after in utero electroporation of plasmids expressing FLAG-DOCK7, and EGFP (green) and mKO2-F (red) fluorescent markers (at E15.5). Images acquired over an 8-h time period are shown; time (in min) is indicated on the top. Note: the cell body of the RGC remains at its original basal position for about 5 h, which is followed by cell division away from the ventricular surface. (AVI 190 kb)

Supplementary Video 3

Example 2 of a DOCK7-overexpressing RGC (cell in upper middle) undergoing bl-to-ap INM in VZ of neocortex. Time-lapse imaging was carried out on acute cortical slices 2 d after in utero electroporation of plasmids expressing FLAG-DOCK7, and EGFP (green) and mKO2-F (red) fluorescent markers (at E15.5). Images acquired over an 8-h time period are shown; time (in min) is indicated on the top. Note: the cell body of the RGC remains at its basal position for about 4.5 h and then moves over a very short distance toward the ventricle, which is followed by cell division away from the ventricular surface. (AVI 235 kb)

Supplementary Video 4

Example of a control scr#1 shRNA–expressing RGC (cell in the middle) undergoing bl-to-ap INM in VZ of neocortex. Time-lapse imaging was carried out on acute cortical slices 2 d after in utero electroporation of plasmids expressing scr#1 shRNA, and EGFP (green) and mKO2-F (red) fluorescent markers (at E15.5). Images acquired over an 8-h time period are shown; time (in min) is indicated on the top. Note: the cell body of the RGC migrates steadily toward the ventricle. After about 5 h, it reaches the ventricular (apical) surface and the cell subsequently divides at the ventricular surface. (AVI 224 kb)

Supplementary Video 5

Example 1 of a Dock7#2 shRNA expressing RGC (cell in the middle) undergoing bl-to-ap INM in VZ of neocortex. Time-lapse imaging was carried out on acute cortical slices 2 d after in utero electroporation of plasmids expressing Dock7#2 shRNA, and EGFP (green) and mKO2-F (red) fluorescent markers (at E15.5). Images acquired over an 8-h time period are shown; time (in min) is indicated on the top. Note: the cell body of the RGC migrates considerably faster to the ventricle surface than that of the control scr#1 shRNA–expressing RGC, where it then remains for about 3 h before the cell undergoes apical mitosis. (AVI 204 kb)

Supplementary Video 6

Example 2 of a Dock7#2 shRNA expressing RGC (cell in the middle) undergoing bl-to-ap INM in VZ of neocortex. Time-lapse imaging was carried out on acute cortical slices 2 d after in utero electroporation of plasmids expressing Dock7#2 shRNA, and EGFP (green) and mKO2-F (red) fluorescent markers (at E15.5). Images acquired over an 8-h time period are shown; time (in min) is indicated on the top. Note: the cell body of the RGC migrates considerably faster to the ventricle surface than that of the control scr#1 shRNA expressing RGC, where it then remains for >4 h before the cell undergoes apical mitosis. (AVI 246 kb)

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Yang, YT., Wang, CL. & Van Aelst, L. DOCK7 interacts with TACC3 to regulate interkinetic nuclear migration and cortical neurogenesis. Nat Neurosci 15, 1201–1210 (2012). https://doi.org/10.1038/nn.3171

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