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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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.
The authors declare no conflict of interest.
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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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