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

• DOI: 10.1073/pnas.1312661110
• Publication Date: 2013-10-08T03:17:51Z
• Authors: Michihiro Toritsuka; Sohei Kimoto; Kazue Muraki; Melissa A. Landek...; Atsuhiro Yoshida; Norio Yamamoto; Yasue Horiuchi; Hideki Hiyama; Katsunori Tajinda; Ni Keni; Elizabeth Illingw...; Takashi Iwamoto; Toshifumi Kishimoto; Akira Sawa; Kenji Tanigaki
• Keywords: Interneuron; DISC1; Neurodevelopmental disorder; Ectopic expression; Knockout mouse

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