Autism spectrum disorder susceptibility gene TAOK2 affects basal dendrite formation in the neocortex

  • A Corrigendum to this article was published on 21 November 2014

Abstract

How neurons develop their morphology is an important question in neurobiology. Here we describe a new pathway that specifically affects the formation of basal dendrites and axonal projections in cortical pyramidal neurons. We report that thousand-and-one-amino acid 2 kinase (TAOK2), also known as TAO2, is essential for dendrite morphogenesis. TAOK2 downregulation impairs basal dendrite formation in vivo without affecting apical dendrites. Moreover, TAOK2 interacts with Neuropilin 1 (Nrp1), a receptor protein that binds the secreted guidance cue Semaphorin 3A (Sema3A). TAOK2 overexpression restores dendrite formation in cultured cortical neurons from Nrp1Sema− mice, which express Nrp1 receptors incapable of binding Sema3A. TAOK2 overexpression also ameliorates the basal dendrite impairment resulting from Nrp1 downregulation in vivo. Finally, Sema3A and TAOK2 modulate the formation of basal dendrites through the activation of the c-Jun N-terminal kinase (JNK). These results delineate a pathway whereby Sema3A and Nrp1 transduce signals through TAOK2 and JNK to regulate basal dendrite development in cortical neurons.

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Figure 1: Distribution of TAOK2 and activated TAOK2 in cultured neurons and the developing cerebral cortex.
Figure 2: TAOK2 downregulation or overexpression affects the differentiation of isolated cortical neurons.
Figure 3: TAOK2 downregulation or overexpression affects basal dendrite arborization and callosal axon projection in the developing cortex.
Figure 4: TAOK2 interacts with Nrp1 to modulate TAOK2 phosphorylation.
Figure 5: TAOK2 and Sema3A modulate the activity of JNK1.
Figure 6: TAOK2 counteracts the dendritic arborization deficit in neurons expressing a deficient receptor for Nrp1 or with Nrp1 downregulation.
Figure 7: Activated JNK1 ameliorates deficient basal dendrite formation after TAOK2 downregulation.

Change history

  • 09 July 2012

    In the version of this article initially published, the scale bar length for Figure 7d was not given. The bar represents 10 μm. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank A. Mungenast, E.J. Kwon, M.H. Cobb (University of Texas Southwestern Medical Center) and Y. Gotoh (University of Tokyo) for critical reading of the manuscript, providing vectors, antibodies, and suggestions. The Simons Foundation Autism Research Initiative supported this work. F.C.d.A. is supported by a postdoctoral fellowship from the Simons Foundation (Simons Center for the Social Brain, Massachusetts Institute of Technology). US National Institutes of Health grant R01 MH59199 to A.L.K. and D.D.G. supported this work. L.-H.T., A.L.K. and D.D.G. are investigators of the Howard Hughes Medical Institute.

Author information

This study was designed, directed and coordinated by F.C.d.A. and L.-H.T. L.-H.T., as the principal investigator, provided conceptual and technical guidance for all aspects of the project. F.C.d.A. planned and performed the in utero electroporations and analyzed the data with A.L.R. and O.D. F.C.d.A. performed and analyzed the immunohistochemistry experiments. K.M. generated and characterized the shRNA constructs. K.M., A.L.R. and D.R. contributed to the neuronal cultures. T.T. performed and analyzed the data from the neuronal cultures of Nrp1Sema− mice. A.L.R., O.D., J.G. and R.M. contributed to the biochemistry experiments. T.S. generated the lentiviral shRNA construct and produced the virus particles. D.D.G. and A.L.K. provided the Nrp1Sema− mouse brains and suggested and commented on the design of the experiments. The manuscript was written by F.C.d.A. and L.-H.T. and commented on by all authors.

Correspondence to Li-Huei Tsai.

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Calderon de Anda, F., Rosario, A., Durak, O. et al. Autism spectrum disorder susceptibility gene TAOK2 affects basal dendrite formation in the neocortex. Nat Neurosci 15, 1022–1031 (2012). https://doi.org/10.1038/nn.3141

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