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

• Published in: Molecular psychiatry Vol. 20; no. 3; pp. 388 - 397
• Main Authors: Durak, O, de Anda, F C, Singh, K K, Leussis, M P, Petryshen, T L, Sklar, P, Tsai, L-H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2015; Nature Publishing Group
• Subjects: 631/378; 692/699/476/1333; 692/699/476/1373; 692/699/476/1799; Actins - genetics; Actins - metabolism; Affective disorders; Animals; Ankyrins; Ankyrins - deficiency; Autism; Behavioral Sciences; Biological Psychology; Bipolar disorder; Carcinoma - pathology; Cell Line, Tumor; Cell Proliferation - genetics; Cells, Cultured; Cerebral Cortex - cytology; Embryo, Mammalian; Female; Gene Expression Regulation, Developmental - genetics; Genetic aspects; Genome-wide association studies; Genomes; Localization; Medicine; Medicine & Public Health; Mental disorders; Mice; Mice, Transgenic; Neural coding; Neurogenesis; Neurogenesis - genetics; Neurons - physiology; Neurosciences; Nuclei (cytology); original-article; Pharmacotherapy; Physiological aspects; Pregnancy; Psychiatry; Risk factors; Schizophrenia; Subcellular Fractions - metabolism; Wnt protein; Wnt proteins; Wnt Proteins - metabolism; Wnt Signaling Pathway - genetics; β-Catenin; United States
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2014.42

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.