Author/EditorToritsuka, Michihiro
Kimoto, Sohei
Muraki, Kazue
Landek-Salgado, Melissa A
Yoshida, Atsuhiro
Yamamoto, Norio
Horiuchi, Yasue
Hiyama, Hideki
Tajinda, Katsunori
Keni, Ni
Illingworth, Elizabeth
Iwamoto, Takashi
Kishimoto, Toshifumi
Sawa, Akira
Tanigaki, Kenji
Alternative Title22q11欠失症候群モデルマウスの神経発達障害には、マイクロRNAが介在するCxcr4/Cxcl12シグナリングの欠損が寄与する
Periodical titleProceedings of the National Academy of Sciences of the United States of America Vol. No. p.
Note (General)type:Thesis
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.
博士(医学)・乙1331号・平成26年3月17日
identifier:Proceedings of the National Academy of Sciences of the United States of America Vol.110 No.43 p.17552-17557
identifier:00278424
identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/2716
identifier:Proceedings of the National Academy of Sciences of the United States of America Vol. No. p., 110(43): 17552-17557
DOIinfo:doi/10.1073/pnas.1312661110
Collection (particular)国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文
Date Accepted (W3CDTF)2015-02-03T05:25:05+09:00
Data Provider (Database)国立国会図書館 : 国立国会図書館デジタルコレクション