Prickle2 and Igsf9b Coordinately Regulate the Cytoarchitecture of the Axon Initial Segment

Cell Struct Funct. 2020 Sep 1;45(2):143-154. doi: 10.1247/csf.20028. Epub 2020 Jul 8.

Abstract

Prickle2 has been identified in genetic studies of subjects with autism spectrum disorder (ASD) and epilepsy, but the pathological mechanism of Prickle2 remains to be fully understood. Proteomic analysis of Prickle2 with mass spectrometry revealed twenty-eight Prickle2 interactors, including immunoglobulin superfamily member 9b (Igsf9b), in the brain. Here, because Igsf9 family proteins are associated with psychiatric diseases and seizures, we studied the physiological interaction between Prickle2 and Igsf9b. Prickle2 colocalized with Igsf9b in cultured hippocampal neurons. Knockdown of Prickle2 affected the subcellular localization of Igsf9b. Interestingly, Igsf9b localized along axonal processes in a pattern opposite to the ASD-related molecule ANK3/AnkG. AnkG is a major component of the axon initial segment (AIS), where a variety of ASD and epilepsy susceptibility proteins accumulate. Igsf9b-knockdown neurons displayed altered AnkG localization. Prickle2 depletion caused defects in AnkG and voltage-gated Na+ channel localization, resulting in altered network activity. These results support the idea that Prickle2 regulates AnkG distribution by controlling the proper localization of Igsf9b. The novel function of Prickle2 in AIS cytoarchitecture provides new insights into the shared pathology of ASD and epilepsy.Key words: Prickle2, Igsf9b, axon initial segment, neuronal excitability, ASD.

Keywords: ASD; Igsf9b; Prickle2; axon initial segment; neuronal excitability.

MeSH terms

  • Animals
  • Ankyrins / genetics
  • Ankyrins / metabolism
  • Autism Spectrum Disorder / genetics
  • Autism Spectrum Disorder / metabolism
  • Axons / metabolism*
  • Epilepsy / genetics
  • Epilepsy / metabolism
  • Hippocampus / metabolism*
  • LIM Domain Proteins / genetics
  • LIM Domain Proteins / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*

Substances

  • Ank3 protein, mouse
  • Ankyrins
  • IgSF9b protein, mouse
  • LIM Domain Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Prickle2 protein, mouse

Grants and funding

This work was supported by Grants-in-Aid for Scientific Research on Innovative Areas: ‘Constructive understanding of multiscale dynamism of neuropsychiatric disorders (19142160)’, grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (KAKENHI grant numbers: JP19142160, JP17921988), a grant-in-aid for “Integrated research on neuropsychiatric disorders” carried out under the Strategic Research Program for Brain Sciences from AMED (grant No. 19dm0207075h0001), and a grant-in-aid from the Hori Sciences & Arts Foundation (FV2019).