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Arl13b-regulated cilia activities are essential for polarized radial glial scaffold formation

Nature Neuroscience volume 16, pages 1000–1007 (2013)Cite this article

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Abstract

The construction of cerebral cortex begins with the formation of radial glia. Once formed, polarized radial glial cells divide either symmetrically or asymmetrically to balance appropriate production of progenitor cells and neurons. Following birth, neurons use the processes of radial glia as scaffolding for oriented migration. Radial glia therefore provide an instructive structural matrix to coordinate the generation and placement of distinct groups of cortical neurons in the developing cerebral cortex. We found that Arl13b, a cilia-enriched small GTPase that is mutated in Joubert syndrome, was critical for the initial formation of the polarized radial progenitor scaffold. Using developmental stage–specific deletion of Arl13b in mouse cortical progenitors, we found that early neuroepithelial deletion of ciliary Arl13b led to a reversal of the apical–basal polarity of radial progenitors and aberrant neuronal placement. Arl13b modulated ciliary signaling necessary for radial glial polarity. Our findings indicate that Arl13b signaling in primary cilia is crucial for the initial formation of a polarized radial glial scaffold and suggest that disruption of this process may contribute to aberrant neurodevelopment and brain abnormalities in Joubert syndrome–related ciliopathies.

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Figure 1: Primary cilia in neuroepithelial cells and cortical progenitors.
Figure 2: Disrupted formation of polarized radial progenitor scaffold in Arl13b mutants.
Figure 3: Disrupted cortical layer formation in Arl13b mutants.
Figure 4: Cortical developmental disruptions in Arl13b mutants.
Figure 5: Arl13b deletion in neuroepithelial cells disrupts radial progenitor scaffold organization and laminar organization of neurons in cerebral cortex.
Figure 6: Altered primary cilia dynamics in Arl13b mutants.
Figure 7: Disrupted localization and signaling of apical complex receptors IgfR1 in Arl13bhnn/hnn cortex.

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Acknowledgements

We thank A.-S. Lamantia, L. Pevny, M. Deshmukh and W. Snider for helpful comments and C.T. Strauss for editing. This research was supported by US National Institutes of Health grants MH060929 to E.S.A. and NS056380 to T.C., a NARSAD Young Investigator Award to H.H., a US National Institutes of Health predoctoral training grant to N.L.U. (T32GM008490) and the confocal imaging core of a National Institute of Neurological Disorders and Stroke institutional center core grant (P30 NS045892).

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Author notes

  1. Holden Higginbotham and Jiami Guo: These authors contributed equally to this work.

Authors and Affiliations

  1. University of North Carolina Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

    Holden Higginbotham, Jiami Guo, Yukako Yokota, Jingjun Li, Nisha Verma, Joshua Hirt, Vladimir Ghukasyan & E S Anton

  2. Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

    Holden Higginbotham, Jiami Guo, Yukako Yokota, Jingjun Li, Nisha Verma, Joshua Hirt, Vladimir Ghukasyan & E S Anton

  3. Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA

    Nicole L Umberger, Chen-Ying Su & Tamara Caspary

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Contributions

E.S.A., H.H., J.G., Y.Y. and T.C. designed the experiments and supervised the project. H.H., J.G., Y.Y., N.L.U., C.-Y.S., J.L., V.G., J.H. and N.V. conducted the experiments and analyzed the data. E.S.A., H.H., J.G. and T.C. wrote the manuscript.

Corresponding authors

Correspondence to Tamara Caspary or E S Anton.

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Supplementary information

Supplementary Figures and Text

Supplementary Figures 1–5 (PDF 15089 kb)

Supplementary Video 1

MRI scan (axial plane) through E12.5 wild-type embryo showing normal CNS organization. (MOV 9651 kb)

Supplementary Video 2

MRI scan (axial plane) through E12.5 mutant embryo showing the perturbance in telencephalic CNS structures in mutants. (MOV 7455 kb)

Supplementary Video 3

Primary cilia dynamics in the ventricular zone. (AVI 7122 kb)

Supplementary Video 4

Primary cilium changes its localization in progenitors. (AVI 2865 kb)

Supplementary Video 5

Wild-type primary cilia dynamics. (AVI 914 kb)

Supplementary Video 6

Arl13b mutant primary cilia dynamics. (AVI 772 kb)

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Higginbotham, H., Guo, J., Yokota, Y. et al. Arl13b-regulated cilia activities are essential for polarized radial glial scaffold formation. Nat Neurosci 16, 1000–1007 (2013). https://doi.org/10.1038/nn.3451

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