Department of Pharmacology and Physiology, George Washington University, Washington, DC 20037, USA.
Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18601-6. doi: 10.1073/pnas.1211507109. Epub 2012 Oct 22.
Interneurons are thought to be a primary pathogenic target for several behavioral disorders that arise during development, including schizophrenia and autism. It is not known, however, whether genetic lesions associated with these diseases disrupt established molecular mechanisms of interneuron development. We found that diminished 22q11.2 gene dosage-the primary genetic lesion in 22q11.2 deletion syndrome (22q11.2 DS)-specifically compromises the distribution of early-generated parvalbumin-expressing interneurons in the Large Deletion (LgDel) 22q11.2DS mouse model. This change reflects cell-autonomous disruption of interneuron migration caused by altered expression of the cytokine C-X-C chemokine receptor type 4 (Cxcr4), an established regulator of this process. Cxcr4 is specifically reduced in LgDel migrating interneurons, and genetic analysis confirms that diminished Cxcr4 alters interneuron migration in LgDel mice. Thus, diminished 22q11.2 gene dosage disrupts cortical circuit development by modifying a critical molecular signaling pathway via Cxcr4 that regulates cortical interneuron migration and placement.
神经元被认为是几种发育过程中出现的行为障碍的主要致病靶点，包括精神分裂症和自闭症。然而，尚不清楚与这些疾病相关的遗传损伤是否会破坏中间神经元发育的既定分子机制。我们发现，22q11.2 缺失综合征（22q11.2DS）中主要的遗传损伤——22q11.2 号染色体区域缺失——导致的 22q11.2 号染色体区域基因剂量减少，特异性地损害了早期产生的表达钙结合蛋白 Parvalbumin 的中间神经元在大型缺失（LgDel）22q11.2DS 小鼠模型中的分布。这种变化反映了细胞自主迁移的中断，是由细胞因子 C-X-C 趋化因子受体 4（Cxcr4）表达改变引起的，Cxcr4 是该过程的一个既定调节因子。Cxcr4 在 LgDel 迁移的中间神经元中特异性减少，遗传分析证实，Cxcr4 的减少改变了 LgDel 小鼠中间神经元的迁移。因此，22q11.2 号染色体区域基因剂量的减少通过改变 Cxcr4 这条关键的分子信号通路，干扰了皮质中间神经元的迁移和定位，从而破坏了皮质回路的发育。
