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

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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 43 Pg. 17552-7 (Oct 22 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 24101523 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• CXCR4 protein, mouse
• Chemokine CXCL12
• Cxcl12 protein, mouse
• Dgcr8 protein, mouse
• MicroRNAs
• RNA-Binding Proteins
• Receptors, CXCR4

Topics

• 22q11 Deletion Syndrome (genetics, metabolism)
• Animals
• Cells, Cultured
• Chemokine CXCL12 (genetics, metabolism)
• Dentate Gyrus (metabolism, pathology)
• Disease Models, Animal
• Gene Expression Profiling
• Gene Knockout Techniques
• HEK293 Cells
• Humans
• Immunohistochemistry
• Interneurons (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• MicroRNAs (genetics, metabolism)
• Nervous System Diseases (genetics, metabolism)
• Oligonucleotide Array Sequence Analysis
• RNA-Binding Proteins (genetics, metabolism)
• Receptors, CXCR4 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (genetics)