Development of the deep cerebellar nuclei: Transcription factors and cell migration from the rhombic lip
Development of the deep cerebellar nuclei: Transcription factors and cell migration from the rhombic lip
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DOI：
10.1523/jneurosci.5203-05.2006
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发表时间：
2006-03-15
影响因子：
5.3
通讯作者：
Hevner, RF
中科院分区：
文献类型：
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作者：
Fink, AJ;Englund, C;Hevner, RF
小脑深核(DCN)是小脑的主要输出中枢，但对其发育过程知之甚少。使用转录因子作为细胞类型特异性标记物，我们发现小鼠的DCN神经元产生于菱形嘴唇，并沿软膜下流向核过渡区(NTZ)迁移。菱形唇源性细胞在进入ntz时依次表达转录因子Pax6、Tbr2和Tbr1。菱形唇源性细胞的一个子集也表达reelin，这是浦肯野细胞迁移的关键调节因素。在器官型切片培养中，菱形唇形是产生细胞的必要条件和充分条件，这些细胞在软膜下流中迁移，进入NTZ，并表达Pax6、Tbr2、Tbr1和Reelin。在发育的后期，外颗粒层取代了硬膜下流，NTZ组织成不同的DCN核。Tbr1在内侧DCN投射神经元中的表达持续到成年期。在有严重小脑畸形的Reeler突变小鼠中，尽管Reelin缺乏，但菱形唇源性细胞迁移到了NTZ。对Tbr1突变小鼠的研究表明，Tbr1在DCN的形态发生中发挥作用，但不是Reelin表达、谷氨酸能分化或传出轴突通路初始形成所必需的。我们的发现揭示了DCN和大脑皮层谷氨酸能神经元产生的转录程序的潜在相似性，并支持小脑神经发生的模型，在该模型中，谷氨酸和GABA能神经元产生于不同的祖细胞隔室。
The deep cerebellar nuclei (DCN) are the main output centers of the cerebellum, but little is known about their development. Using transcription factors as cell type-specific markers, we found that DCN neurons in mice are produced in the rhombic lip and migrate rostrally in a subpial stream to the nuclear transitory zone (NTZ). The rhombic lip-derived cells express transcription factors Pax6, Tbr2, and Tbr1 sequentially as they enter the NTZ. A subset of rhombic lip-derived cells also express reelin, a key regulator of Purkinje cell migrations. In organotypic slice cultures, the rhombic lip was necessary and sufficient to produce cells that migrate in the subpial stream, enter the NTZ, and express Pax6, Tbr2, Tbr1, and reelin. In later stages of development, the subpial stream is replaced by the external granular layer, and the NTZ organizes into distinct DCN nuclei. Tbr1 expression persists to adulthood in a subset of medial DCN projection neurons. In reeler mutant mice, which have a severe cerebellar malformation, rhombic lip-derived cells migrated to the NTZ, despite reelin deficiency. Studies in Tbr1 mutant mice suggested that Tbr1 plays a role in DCN morphogenesis but is not required for reelin expression, glutamatergic differentiation, or the initial formation of efferent axon pathways. Our findings reveal underlying similarities in the transcriptional programs for glutamatergic neuron production in the DCN and the cerebral cortex, and they support a model of cerebellar neurogenesis in which glutamatergic and GABAergic neurons are produced from separate progenitor compartments.