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Ankyrin-G regulates neurogenesis and Wnt signaling by altering the subcellular localization of β-catenin

Molecular Psychiatry volume 20, pages 388–397 (2015)Cite this article

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Abstract

Ankyrin-G is a scaffolding protein required for the formation of the axon initial segment in neurons. Recent genome-wide association studies and whole-exome sequencing have identified ANK3, the gene coding for ankyrin-G, to be a risk gene for multiple neuropsychiatric disorders, such as bipolar disorder, schizophrenia and autism spectrum disorder. Here, we describe a novel role for ankyrin-G in neural progenitor proliferation in the developing cortex. We found that ankyrin-G regulates canonical Wnt signaling by altering the subcellular localization and availability of β-catenin in proliferating cells. Ankyrin-G loss-of-function increases β-catenin levels in the nucleus, thereby promoting neural progenitor proliferation. Importantly, abnormalities in proliferation can be rescued by reducing Wnt pathway signaling. Taken together, these results suggest that ankyrin-G is required for proper brain development.

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Acknowledgements

We thank Drs A Mungenast, Y Mao, A Bero and J Gräff for critical reading of the manuscript. We are thankful to Y Mao, D Rei, T Soda, P Giusti and J Gräff for technical help and suggestions with the project. Super8XTOPFLASH luciferase reporter construct was a kind gift from Dr Randall Moon (University of Washington). We also thank ME Taylor and AS Gomes for their help with production of Ank3 mice. OD is a Henry Singleton (1940) Fellow (Brain and Cognitive Sciences, Massachusetts Institute of Technology). FCdA was supported by a postdoctoral fellowship from the Simons Foundation (Simons Center for the Social Brain, Massachusetts Institute of Technology). This work was partially supported by an NIH RO1 Grant (MH091115) to L-HT, a grant from the Stanley Medical Research Institute to L-HT and TLP, and the Howard Hughes Medical Institute.

Author information

Author notes

  1. F C de Anda

    Present address: 7Current Address: Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,

  2. K K Singh

    Present address: 8Current Address: Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.,

  3. M P Leussis

    Present address: 9Current Address: Department of Psychology, Emmanuel College, Boston, MA, USA.,

  4. O Durak and F C de Anda: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA,

    O Durak, F C de Anda, K K Singh & L-H Tsai

  2. Center for Human Genetic Research and Department of Psychiatry, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA,

    M P Leussis & T L Petryshen

  3. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    M P Leussis & T L Petryshen

  4. Stanley Center for Psychiatric Research, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA

    M P Leussis & T L Petryshen

  5. Division of Psychiatric Genomics, Departments of Psychiatry, Neuroscience and Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA

    P Sklar

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Correspondence to L-H Tsai.

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Durak, O., de Anda, F., Singh, K. et al. Ankyrin-G regulates neurogenesis and Wnt signaling by altering the subcellular localization of β-catenin. Mol Psychiatry 20, 388–397 (2015). https://doi.org/10.1038/mp.2014.42

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