Meechan Daniel W, Tucker Eric S, Maynard Thomas M, LaMantia Anthony-Samuel
Department of Cell and Molecular Physiology and Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16434-45. doi: 10.1073/pnas.0905696106. Epub 2009 Sep 10.
The 22q11 deletion (or DiGeorge) syndrome (22q11DS), the result of a 1.5- to 3-megabase hemizygous deletion on human chromosome 22, results in dramatically increased susceptibility for "diseases of cortical connectivity" thought to arise during development, including schizophrenia and autism. We show that diminished dosage of the genes deleted in the 1.5-megabase 22q11 minimal critical deleted region in a mouse model of 22q11DS specifically compromises neurogenesis and subsequent differentiation in the cerebral cortex. Proliferation of basal, but not apical, progenitors is disrupted, and subsequently, the frequency of layer 2/3, but not layer 5/6, projection neurons is altered. This change is paralleled by aberrant distribution of parvalbumin-labeled interneurons in upper and lower cortical layers. Deletion of Tbx1 or Prodh (22q11 genes independently associated with 22q11DS phenotypes) does not similarly disrupt basal progenitors. However, expression analysis implicates additional 22q11 genes that are selectively expressed in cortical precursors. Thus, diminished 22q11 gene dosage disrupts cortical neurogenesis and interneuron migration. Such developmental disruption may alter cortical circuitry and establish vulnerability for developmental disorders, including schizophrenia and autism.
22q11缺失（或迪乔治）综合征（22q11DS）是人类22号染色体上1.5至3兆碱基半合子缺失的结果，会导致在发育过程中出现的“皮质连接性疾病”的易感性显著增加，包括精神分裂症和自闭症。我们发现，在22q11DS小鼠模型中，1.5兆碱基22q11最小关键缺失区域内缺失的基因剂量减少，会特异性损害大脑皮质中的神经发生及随后的分化。基底祖细胞而非顶端祖细胞的增殖受到破坏，随后，第2/3层而非第5/6层投射神经元的频率发生改变。这种变化与小白蛋白标记的中间神经元在上层和下层皮质层中的异常分布平行。Tbx1或Prodh（与22q11DS表型独立相关的22q11基因）的缺失不会类似地破坏基底祖细胞。然而，表达分析表明，还有其他22q11基因在皮质前体细胞中选择性表达。因此，22q11基因剂量减少会破坏皮质神经发生和中间神经元迁移。这种发育破坏可能会改变皮质回路，并导致包括精神分裂症和自闭症在内的发育障碍的易感性增加。
