Lmx1a regulates fates and location of cells originating from the cerebellar rhombic lip and telencephalic cortical hem
Lmx1a regulates fates and location of cells originating from the cerebellar rhombic lip and telencephalic cortical hem
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DOI：
10.1073/pnas.0910786107
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发表时间：
2010-06-08
影响因子：
11.1
通讯作者：
Millen, Kathleen J.
中科院分区：
文献类型：
--
作者：
Chizhikov, Victor V.;Lindgren, Anne G.;Millen, Kathleen J.
小脑菱形唇和端脑皮质血脑位于背侧的生发区，对中枢神经系统的神经元多样性有很大贡献，但驱动这些区域内神经发生的机制尚不清楚。使用野生型和 Lmx1a(-/-) 小鼠的遗传命运图谱，我们证明 Lmx1a 是这两个生发区内细胞命运决定的关键调节因子。在发育中的小脑中，Lmx1a 在顶板中表达，需要将顶板谱系与神经元菱形唇衍生物分离。此外，Lmx1a 在菱形唇祖细胞的子集中表达，这些祖细胞产生的颗粒细胞主要局限于小脑后蚓部。在缺乏 Lmx1a 的情况下，这些细胞过早地离开菱形唇并过度迁移到前蚓部。这种过度迁移与 Lmx1a(-/-) 小鼠菱形唇的过早退化和后蚓部发育不全有关。这些数据揭示了小脑菱形唇的分子组织，并介绍了 Lmx1a 作为菱形唇细胞命运决定的重要调节因子，这对于维持整个菱形唇和正常小脑形态发生至关重要。在发育中的端脑中，Lmx1a 在皮质下缘中表达，在皮质下缘缺失的情况下，皮质下缘祖细胞会对邻近的海马体做出过度贡献，而不是产生 Cajal-Retzius 神经元。因此，Lmx1a 活性对于小脑菱形唇和端脑皮质下缘细胞的正常产生至关重要。
The cerebellar rhombic lip and telencephalic cortical hemare dorsally located germinal zones which contribute substantially to neuronal diversity in the CNS, but the mechanisms that drive neurogenesis within these zones are ill defined. Usinggenetic fate mapping in wild-type and Lmx1a(-/-) mice, we demonstrate that Lmx1a is a critical regulator of cell-fate decisions within both these germinal zones. In the developing cerebellum, Lmx1a is expressed in the roof plate, where it is required to segregate the roof plate lineage from neuronal rhombic lip derivatives. In addition, Lmx1a is expressed in a subset of rhombic lip progenitors which produce granule cells that are predominantly restricted to the cerebellar posterior vermis. In the absence of Lmx1a, these cells precociously exit the rhombic lip and overmigrate into the anterior vermis. This overmigration is associated with premature regression of the rhombic lip and posterior vermis hypoplasia in Lmx1a(-/-) mice. These data reveal molecular organization of the cerebellar rhombic lip and introduce Lmx1a as an important regulator of rhombic lip cell-fate decisions, which are critical for maintenance of the entire rhombic lip and normal cerebellar morphogenesis. In the developing telencephalon Lmx1a is expressed in the cortical hem, and in its absence cortical hem progenitors contribute excessively to the adjacent hippocampus instead of producing Cajal-Retzius neurons. Thus, Lmx1a activity is critical for proper production of cells originating from both the cerebellar rhombic lip and the telencephalic cortical hem.