Origin of climbing fiber neurons and their developmental dependence on Ptf1a
Origin of climbing fiber neurons and their developmental dependence on Ptf1a
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DOI：
10.1523/jneurosci.1423-07.2007
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发表时间：
2007-10-10
影响因子：
5.3
通讯作者：
Hoshino, Mikio
中科院分区：
文献类型：
--
作者：
Yamada, Mayumi;Terao, Mami;Hoshino, Mikio
下橄榄核（ION）中的攀爬纤维（CF）神经元将轴突延伸至浦肯野细胞，在调节小脑功能中发挥着至关重要的作用。然而，人们对它们的确切出生地和发育分子机制知之甚少。在这里，我们描述了 CF 神经元谱系的起源以及 Ptf1a（胰腺转录因子 1a）在 CF 神经元发育中的参与。发现 Ptf1a 蛋白在胚胎尾后脑神经上皮的离散背外侧区域表达。由于 Ptf1a 的表达不与其他转录因子（例如 Math1（小鼠无调性同源物 1）和 Neurogenin1）重叠，这些转录因子被建议定义尾后脑神经上皮内的结构域（Landsberg 等，2005），因此我们将神经上皮区域命名为 Ptf1a 结构域。对 Ptf1a 基因座表达 β-半乳糖苷酶的小鼠的分析表明，CF 神经元源自 Ptf1a 结构域。相反，小脑前神经元的逆行标记表明苔藓纤维神经元并非源自表达 Ptf1a 的祖细胞。我们可以观察胚胎发生过程中 CF 神经元从 Ptf1a 结构域到 ION 的详细迁移路径。在 Ptf1a 无效突变体中，从该结构域产生的假定的未成熟 CF 神经元无法适当迁移或分化，导致 ION 形成失败。在突变后脑中观察到凋亡细胞。此外，Ptf1a 谱系中一些细胞的命运在 Ptf1a 无效突变体中转变为苔藓纤维神经元。这些发现阐明了 CF 神经元的精确起源，并表明 Ptf1a 在发育过程中控制着它们的命运、存活、分化和迁移。
Climbing fiber (CF) neurons in the inferior olivary nucleus (ION) extend their axons to Purkinje cells, playing a crucial role in regulating cerebellar function. However, little is known about their precise place of birth and developmental molecular machinery. Here, we describe the origin of the CF neuron lineage and the involvement of Ptf1a (pancreatic transcription factor 1a) in CF neuron development. Ptf1a protein was found to be expressed in a discrete dorsolateral region of the embryonic caudal hindbrain neuroepithelium. Because expression of Ptf1a is not overlapping other transcription factors such as Math1 (mouse atonal homolog 1) and Neurogenin1, which are suggested to define domains within caudal hindbrain neuroepithelium (Landsberg et al., 2005), we named the neuroepithelial region the Ptf1a domain. Analysis of mice that express beta-galactosidase from the Ptf1a locus revealed that CF neurons are derived from the Ptf1a domain. In contrast, retrograde labeling of precerebellar neurons indicated that mossy fiber neurons are not derived from Ptf1a-expressing progenitors. We could observe a detailed migratory path of CF neurons from the Ptf1a domain to the ION during embryogenesis. In Ptf1a null mutants, putative immature CF neurons produced from this domain were unable to migrate or differentiate appropriately, resulting in a failure of ION formation. Apoptotic cells were observed in the mutant hindbrain. Furthermore, the fate of some cells in the Ptf1a lineage were changed to mossy fiber neurons in Ptf1a null mutants. These findings clarify the precise origin of CF neurons and suggest that Ptf1a controls their fate, survival, differentiation, and migration during development.