Deficits in microRNA-mediated Cxcr4/Cxcl12 signaling in neurodevelopmental deficits in a 22q11 deletion syndrome mouse model

Michihiro Toritsuka, Sohei Kimoto, Kazue Muraki, Melissa A. Landek-Salgado, Atsuhiro Yoshida, Norio Yamamoto, Yasue Horiuchi, Hideki Hiyama, Katsunori Tajinda, Ni Keni, Elizabeth Illingworth, Takashi Iwamoto, Toshifumi Kishimoto, Akira Sawa, Kenji Tanigaki

Research output: Contribution to journalArticle

Abstract

22q11 deletion syndrome (22q11DS) frequently accompanies psychiatric conditions, some of which are classified as schizophrenia and bipolar disorder in the current diagnostic categorization. However, it remains elusive how the chromosomal microdeletion leads to the mental manifestation at the mechanistic level. Here we show that a 22q11DS mouse model with a deletion of 18 orthologous genes of human 22q11 (Df1/+ mice) has deficits in migration of cortical interneurons and hippocampal dentate precursor cells. Furthermore, Df1/+ mice show functional defects in Chemokine receptor 4/Chemokine ligand 12 (Cxcr4/Cxcl12; Sdf1) signaling, which reportedly underlie interneuron migration. Notably, the defects in interneuron progenitors are rescued by ectopic expression of Dgcr8, one of the genes in 22q11 microdeletion. Furthermore, heterozygous knockout mice for Dgcr8 show similar neurodevelopmental abnormalities as Df1/+ mice. Thus, Dgcr8- mediated regulation of microRNA is likely to underlie Cxcr4/Cxcl12 signaling and associated neurodevelopmental defects. Finally, we observe that expression of CXCL12 is decreased in olfactory neurons from sporadic cases with schizophrenia compared with normal controls. Given the increased risk of 22q11DS in schizophrenia that frequently shows interneuron abnormalities, the overall study suggests that CXCR4/CXCL12 signaling may represent a common downstream mediator in the pathophysiology of schizophrenia and related mental conditions.

Original languageEnglish (US)
Pages (from-to)17552-17557
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number43
DOIs
StatePublished - Oct 22 2013

Keywords

  • Dentate gyrus
  • Hippocampus

ASJC Scopus subject areas

  • General

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  • Cite this

    Toritsuka, M., Kimoto, S., Muraki, K., Landek-Salgado, M. A., Yoshida, A., Yamamoto, N., Horiuchi, Y., Hiyama, H., Tajinda, K., Keni, N., Illingworth, E., Iwamoto, T., Kishimoto, T., Sawa, A., & Tanigaki, K. (2013). Deficits in microRNA-mediated Cxcr4/Cxcl12 signaling in neurodevelopmental deficits in a 22q11 deletion syndrome mouse model. Proceedings of the National Academy of Sciences of the United States of America, 110(43), 17552-17557. https://doi.org/10.1073/pnas.1312661110