SOX5 postmitotically regulates migration, postmigratory differentiation, and projections of subplate and deep-layer neocortical neurons
SOX5 postmitotically regulates migration, postmigratory differentiation, and projections of subplate and deep-layer neocortical neurons
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DOI：
10.1073/pnas.0806791105
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发表时间：
2008-10-14
影响因子：
11.1
通讯作者：
Sestan, Nenad
中科院分区：
文献类型：
--
作者：
Kwan, Kenneth Y.;Lam, Mandy M. S.;Sestan, Nenad
新皮质投射神经元呈现出层特异性的分子特征和轴突连接。在此我们表明，早产生的板下神经元和深层神经元的分子特性并非仅仅在产生期间或之后不久获得，而是由SOX5介导进行渐进性的有丝分裂后精细化。Fezf2和Bcl11b在新迁移后的早产生神经元的所有亚型中短暂表达，随后在第6层和板下神经元中下调，从而建立它们在出生后富集于第5层的模式。在Sox5缺失小鼠中，这种下调被破坏，第6层和板下神经元维持一种未成熟的分化状态，在出生后异常表达这些基因。与这种破坏一致的是，SOX5结合并抑制Fezf2附近的一个保守增强子。Sox5缺失的新皮质表现出前板分隔失败以及早产生神经元的层状反转，第5层皮质下轴突缺失，以及板下和第6层皮质丘脑轴突错误地投射到下丘脑。因此，SOX5在有丝分裂后调节板下和深层神经元的迁移、迁移后分化以及皮质下投射。
Neocortical projection neurons exhibit layer-specific molecular profiles and axonal connections. Here we Show that the molecular identities of early-born subplate and deep-layer neurons are not acquired solely during generation or shortly thereafter but undergo progressive postmitotic refinement mediated by SOX5. Fezf2 and Bcl11b, transiently expressed in all subtypes of newly postmigratory early-born neurons, are subsequently downregulated in layer 6 and subplate neurons, thereby establishing their layer 5-enriched postnatal patterns. In Sox5-null mice, this downregulation is disrupted, and layer 6 and subplate neurons maintain an immature differentiation state, abnormally expressing these genes postnatally. Consistent with this disruption, SOX5 binds and represses a conserved enhancer near Fezf2. The Sox5-null neocortex exhibits failed preplate partition and laminar inversion of early-born neurons, loss of layer 5 subcerebral axons, and misrourting of subplate and layer 6 corticothalamic axons to the hypothalamus. Thus, SOX5 postmitotically regulates the migration, postmigratory differentiation, and subcortical projections of subplate and deep-layer neurons.