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

Mol Psychiatry. 2015 Mar;20(3):388-97. doi: 10.1038/mp.2014.42. Epub 2014 May 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Actins / metabolism*
  • Animals
  • Ankyrins / deficiency
  • Carcinoma / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Embryo, Mammalian
  • Female
  • Gene Expression Regulation, Developmental / genetics
  • Mice
  • Mice, Transgenic
  • Neurogenesis / genetics*
  • Neurons / physiology*
  • Pregnancy
  • Subcellular Fractions / metabolism*
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway / genetics*

Substances

  • Actins
  • Ank3 protein, mouse
  • Ankyrins
  • Wnt Proteins