Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome
Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome
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DOI：
10.1073/pnas.0905696106
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发表时间：
2009-09-22
影响因子：
11.1
通讯作者：
LaMantia, Anthony-Samuel
中科院分区：
文献类型：
--
作者：
Meechan, Daniel W.;Tucker, Eric S.;LaMantia, Anthony-Samuel
22 q11缺失（或DiGeorge）综合征（22 q11 DS）是人类22号染色体上1.5至3兆半合子缺失的结果，导致对“皮质连接疾病”的易感性急剧增加，这些疾病被认为是在发育过程中出现的，包括精神分裂症和自闭症。我们发现，在22 q11 DS的小鼠模型中，在1.5兆碱基22 q11最小关键缺失区中缺失的基因的剂量减少特别会损害大脑皮层的神经发生和随后的分化。基底而非顶端祖细胞的增殖被破坏，随后，第2/3层投射神经元而非第5/6层投射神经元的频率被改变。这种变化是由异常分布的小白蛋白标记的中间神经元在上，下皮层。Tbx 1或Tbxh（22 q11基因与22 q11 DS表型独立相关）的缺失不会类似地破坏基础祖细胞。然而，表达分析暗示额外的22 q11基因，选择性地表达在皮质前体。因此，减少22 q11基因剂量破坏皮质神经发生和中间神经元迁移。这种发育中断可能会改变皮质回路，并建立发育障碍的脆弱性，包括精神分裂症和自闭症。
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.